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Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the LabPaul Riley PhD MBA Diagnostica Stago Inc

Learning Objectives

Describe the basic pathophysiology of DIC

Demonstrate a diagnostic and management approach for DIC

Compare markers of thrombin amp plasmin generation in DIC including D-Dimer fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs)

Correlate DIC theory and testing to specific clinical cases

DIC = Death is Coming

What is Hemostasis

Blood Circulation

ARTERIES

VEINS

Occurs through blood vessels

The heart pumps the blood

Arteries carry oxygenated blood away from the heart under high pressure

Veins carry de-oxygenated blood back to the heart under low pressure

Hemostasis

The mechanism that maintains blood fluidity

Keeps a balance between bleeding and clotting

2 major roles Stop bleeding by repairing holes in blood vessels Clean up the inside of blood vessels Removes temporary clot that stopped bleeding Sweeps off needless deposits that may cause blood flow

blockages

Bleeding =

Hemorrhage

Blood clot =

Thrombosis

Two Major Diseases Linked to Hemostatic Abnormalities

Physiology of Hemostasis

Wound Sealing

EFFRACbreak in vessel

FIBRINOLYSIS

clot destruction

PRIMARYHEMOSTASIS

PLASMATICCOAGULATION

strong clot

wound sealing blood flow plusmn stopped

The Three Steps of Hemostasis

Primary Hemostasis Interaction between vessel wall platelets and adhesive proteins platelet clot

Coagulation Consolidation of the platelet thrombus insoluble fibrin net

bull Coagulation factors and inhibitors

Fibrinolysis Clot lysis clot is digested

bull Fibrinolytic activators and inhibitors

Vessel Wall

Intact endothelium non thrombogenic Synthesis of vasodilators (prostacyclin) No reaction either with platelets or factors

Sub endotheliumTissue Endothelium

blood

When a vessel wall is damaged Exposure of the subendothelium Platelet adhesion Initiation of the mechanisms of coagulation and fibrinolysis

PlateletsFactors

Sub endotheliumTissue Endothelium

blood

Vessel Wall Damage

Aim is to clog the damaged vessel ( asymp bricks without cement )

Primary Hemostasis

Platelet Structure UnactivatedActivated

GpIb-IX-V

GpIIb-IIIa

α granules (raw materials)PF4 β-TG Fibrinogen VWF Factor V and PAI-1

dense granules (energy and glue)ATP ADP SerotoninCa2+ Mg2+ P

Hillman Robert S Ault Kenneth A Rinder Henry M Hematology in Clinical Practice 4th Edition McGraw-Hill New York NY 2005

Primary Hemostasis

2) activation2nd shape changeamp release

platelet at rest 1) adhesion1st shape change

3) aggregation(not reversible)

Vasoconstriction occurs first

Platelets then aggregate on the break in the vessel wall

Primary Hemostasis AssaysRoutine Platelet count PT APTT TT

Follow-up von Willebrand Factor Antigen determination Activity Factor VIII PFA-100 Platelet aggregation studies

SpecializedSend Out Activation markers (b-TG PF4 GPV) Specialized tests for platelet function

Aim is to strengthen the platelet plug

Coagulation

Coagulation is a balancebetween pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis

THROMBIN

Fibrinogen Fibrin

bull Triggering agentsbull pro-enzyme enzyme (serine-protease FIIa FVIIa FIXa FXa)bull Cofactors (FVa amp FVIIIa)

bull Serine-protease inhibitor Antithrombin (AT) bull Cofactorsinhibitors Protein C Sbull Tissue factor pathway inhibitor (TFPI)

Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

Coagulation Cascade Schematic

Coagulation factors

Historic name

Fibrinogen

Prothrombin

Proaccelerin

Proconvertin

Anti-hemophilic factor A

Anti-hemophilic factor B

Stuart factor

Rosenthal factor

Hageman factor

Fibrin Stabilizing Factor

Factor

I

II

V

VII

VIII

IX

X

XI

XII

XIII

Function

Substrate

Pro-enzyme

Pro-cofactor

Pro-enzyme

Pro-cofactor

Pro-enzyme

Pro-enzyme

Pro-enzyme

Pro-enzyme

Pro-enzyme

Pro-enzyme = Zymogen activation Active Enzyme

Coagulation Assay Mechanisms

aPTT Based

PT Based

PT Based

Fibrin Under Microscope

Weisel JW Structure of fibrin impact on clot stability J Thromb Haemost 2007 5 Suppl 1 116-24

Low thrombin concentration

High thrombin concentration

Fibrin Formation

Soluble FibrinPolymer

ThrombinFibrinogen

FM+ fibrinopeptides A amp B

Stabilized Fibrin clot(not soluble)

ThrombinXIII XIIIa

(Digestion of Fibrin)

Fibrinolysis

Fibrinolysis Overview

Destroys fibrin fibers

Destroys the scab (dried wound)

Maintains vessel integrity

Fibrinolysis Overview

Fibrin =cement fibers

Plasmin

Plasmin digests fibrin

t-PA

Pro Urokinase

Urokinase

PAI-1PAI-1

Plasminogen Plasmin

1st Step

2nd Step

Fibrinolysis Cascade

t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin

Extrinsic pathway(endothelia l cells)

Intrinsic pathway(plasma)

Fibrin clot

D-dimerFibrin degradation products

Fibrin

TAFIa

APAntiplasmin(amp a2-MG)

PK Kallikrein

XII

Fibrinolysis Releases D-dimers

D-dimer presence fibrin has been formed and digested in patients body

Normal D-dimer level no thrombosis occurred in the patient

Basic Pathophysiology of DIC

Disseminated Intravascular Coagulation (DIC)

Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management

Clinical Manifestations of DICOrgan Ischemic Hemorrhagic

Skin Pupura Fulminans Petechiae

Gangrene Echymoses

Acral cyanosis Oozing

CNS Deliriumcoma Intracranial

Infarcts Bleeding

Renal OliguriaAzotemia Hematuria

Cortical Necrosis

Cardiovascular Myocardial dysfunction

Pulmonary DyspneaHypoxia Hemorrhagic lung

Infarct

Gastrointestinal Ulcers infarcts Massive hemorrhage

Endocrine Adrenal infarcts

Purpura Fulminans with DIC Due to Meningococcal Sepsis

Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

Clinical Conditions Associated With DIC

Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

Frequency of DIC in Selected Disease States

Disease Frequency

Gram-negative sepsis 30-50

Severe trauma and systemic inflammation 50-70

Metastasized tumors 15

Abruptio placentaamniotic fluid embolism 50

Severe preeclampsia 7

Giant hemangioma 25

Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017

Underlying Diseases in DIC Patients

In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively

Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

Epidemiology of DIC

Impact of DIC Status on Mortality - 1

Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8

Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC

Impact of DIC Status on Mortality - 2

Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients

Impact of Age on Mortality in DIC Patients

Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)

Pathophysiology of DIC

Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

Pathogenesis of DIC in Sepsis

Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15

Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC

Host Response in Severe Sepsis

Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral

Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

Organ Failure in Severe Sepsis

Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure

Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51

Mechanism of DIC in Organ Failure

Underlying condition(sepsis trauma)

Cytokines

TF-mediatedactivation of coagulation

Depression of inhibitory systems

Reducesfibrinolysis

Fibrin deposition

Organ failure

Inadequate fibrin removal

Fibrinformation

Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )

Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705

Interaction of Inflammation and Coagulation in Sepsis

Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines

Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

Mechanism of Multiple Organ Failure in DIC

Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

lipopolysaccharides

cytokines

coagulation activation

mononuclear cell

tissue factor

Diverse and Opposing Effects of Thrombin

Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

Coagulation and Fibrinolysis in DIC

Soluble fibrin Polymer

XIIIa

D-Dimer

E

Fibrin clot

Fibrin Degradation Products

Fibrinogen Thrombin

Fibrinogen Degradation

Products

D E

Plasmin

DFM + fibrinopeptides

Soluble FM ComplexesPre-throm

boticPost-throm

botic

Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

Mechanism of DIC

THROMBOSIS

Fibrin

Blood activationEndothelial lysisTF expression

BLEEDING

FDPs

D-Dimer

Plasmin

Pathophysiology of DIC

1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

thromboplastin influx of activated cells (monocytes macrophages)

Results in an intravascular deposition of fibrin

Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

Second step Consumption and depletion of coagulation factors inhibitors (Protein C

Protein S AT) and platelets Local fibrinolytic response

bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

FDP and D-Dimer

Bleeding

Pathophysiology of DIC - Mechanism

Systemic activation of coagulation

Intravasculardepositionof fibrin

Thrombosis of small and midsize vessels

and organ failure

Depletion of platelets and

coagulation factors

Bleeding

Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

Pathophysiology of DIC ndash 2 Types of Clinical pictures

Chronic = non - overt DICMay be unrecognized clinically

Acute = overt DIClife threatening bleedingor multiple organ failure

Sub-Acute and Non-Overt DIC Clinical Findings

Compensated non-overt DIC Steady low level or intermittent activation

bull Compensated by increased production of coagulation components and platelets

Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

Risk of decompensation leading to overt DIC

Pathophysiology of Overt DIC

Massive activation of coagulation and fibrinolysis

Does not allow for compensatory efforts

Rapid depletion of coagulation factors inhibitors and platelets

Thrombosis multiple organ failures

Bleeding complications and shock

Physiopathology of DIC ndash Overt DIC Findings

Thrombin generation

Thrombosis

Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

Plasmin generationHemorrhage

bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

bull Tachycardia hypotension edema

Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

Pathogenesis Pathways in DIC

Cytokines

TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

fibrin inadequateformation fibrin removal

Fibrin deposition

Inflammation

Coagulation

Stago Celebrates Lab Week 2017

NA

Stago 247 Educational Webinar Sites

wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

Stago Educational Apps

HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

BREAK

Diagnostic and Management Approach for DIC

Diagnosis of DIC

Clinical diagnosis is obvious in cases of overt DIC

Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

Lab Diagnosis of DIC ndash Markers of Factor Consumption

Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

Important to recognize simultaneous formation of thrombin and plasmin

Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

Lab Diagnosis of DIC ndash Screening Tests

Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

fibrinogen level) repeat testing assesses progression

Screening tests not clinically specific or sensitive for DIC

Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

Laboratory Changes in Overt DIC

DIC Diagnostic Practices Over Time

Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

British Journal of Haematology Overt DIC Score

Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

ISTH Step by Step DIC Algorithm

Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

US Based Validation of ISTH DIC Score

When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

Differential Diagnosis in DIC

aHUS atypical hemolytic uremic syndrome

HUS hemolytic uremic syndrome

HIT heparin-induced thrombocytopenia

ITP immune thrombocytopenic purpura

TTP thrombotic thrombocytopenic purpura

DIC and MAHA

Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

DIC Management Goals

Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

DIC Management and Treatment

Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

DIC Management Strategies

Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

Anticoagulant Factor Concentrate Treatment

Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

Anticoagulant Factor Concentrate Treatment Trials

Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

Markers of Thrombin amp Plasmin Generation in DIC

D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

Cut-off value

Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

degradation products Sensitive assay typically with cutoff adapted for DIC

D-dimer FDPs and DIC

D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

Follow Up of DIC State of Disease

Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

FMD-Dimer in DIC Major Differences

onset of thrombosis

days

Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

of Abnormal Results in Patients with Confirmed and Suspected DIC

0

20

40

60

80

100

94 85 90N = 62

Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

Positivity of Test Results ISTH Score and Disease State

Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

Red bar positive for 2 points of DIC score

Pink bar positive for 1-2 points of DIC score

HT hematopoietic tumor

IF infection

SC solid cancer

Markers in Patients with or without DIC

Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

HT hematopoietic tumorIF infectionSC solid cancer

Comparing an Automated FM vs Manual FSP Test

Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

Automated (Mitsubishi) vs Automated (Stago)

In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

Diagnostic Performance of FM and D-dimer in DIC

Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

Diagnostic Performance of FM and D-dimer in DIC

Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

Diagnostic Performance of FM and D-dimer in DIC

Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

Diagnostic Performance of FM and D-dimer in DIC

Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

Diagnostic Performance of FM and D-dimer in DIC

Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

Diagnostic Performance of FM and D-dimer in DIC

Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

Diagnostic Performance of FM and D-dimer in DIC

Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

Non Overt DIC Overt DIC

AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

Trends in Markers of DIC for Different Patients

Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

Trends in Markers of DIC for Different Patients

Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

28 day outcome survival

28 day outcome death

Determination of Cutoffs of FM and D-dimer in DIC

Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

Determination of Cutoffs of FM and D-dimer in DIC

Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

DIC Case Studies

Case Study 1 - Presentation

18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

WBC count 77 KμL 423 ndash 907 x KμL

RBC count 17 MμL 137 ndash 175 x MμL

Hemoglobin 67 gdL 137 ndash 175 gdL

Hematocrit 195 401 ndash 510

MCV 95 fL 790 ndash 922 fL

MPV 12 fL 94 ndash 124 fL

Platelet count 9 KμL 161 ndash 347 KμL

Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

Lymphocytes monocytes eosinophils basophils all below normal range

PT 47 sec (corrected on mixing study) 116 ndash 152 sec

APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

Case Study 1 ndash Microscopy

Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

DIC due to TF release by APL blasts

Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

Transfusions to replace factors along with platelets and RBCs during APL treatment

Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

Case Study 2 ndash Presentation

TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

PT 30 sec 113 ndash 146 sec

APTT 75 sec 25 ndash 34 sec

D-dimer 078 microgml FEU lt050 microgml FEU

Fibrinogen 92 mgdl 150-400 mgdl

pH 728 738 to 742

PaO2 570 mmHg 80-100 mmHg

WBC 33 times 103mm3 40-11 times 103mm3

ALT 111 IUL 0ndash34 IUL

AST 61 IUL 0ndash34 IUL

BUN 303 mgdL 08-13 mgdL

Case Study 2 ndash Lab Results

Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

Case Study 2 ndash Diagnosis

60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

Case Study 3 ndash Presentation

TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

PT 228 sec 113 ndash 146 sec

APTT 45 sec 25 ndash 34 sec

D-dimer 080 microgml FEU lt050 microgmL FEU

Fibrinogen 82 mgdL 150-400 mgdL

FV Normal 70-120

FVII Normal 55-170

FVIII Normal 60-150

Protein C Normal 70-130

Hb 134 gdL 14-16 gdL

WBC 81 times 103mm3 40-11 times 103mm3

ALT 32 IUL 0ndash34 IUL

AST 28 IUL 0ndash34 IUL

BUN 09 mgdL 08-13 mgdL

Case Study 3 ndash Lab Results

Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

Case Study 3 ndash Diagnosis and Therapy

Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

Case Study 4 ndash Presentation

TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

PT 28 sec 113 ndash 146 sec

APTT 71 sec 25 ndash 34 sec

D-dimer 31 microgmL FEU lt050 microgml FEU

Fibrinogen 92 mgdL 150-400 mgdl

FV Normal 70-120

FVII Normal 55-170

FVIII Normal 60-150

Protein C Normal 70-130

Hb 158 gdL 14-16 gdL

WBC 71 times 103mm3 40-11 times 103mm3

ALT 60 IUL 0ndash34 IUL

AST 47 IUL 0ndash34 IUL

BUN 38 mgdL 08-13 mgdL

Case Study 4 ndash Lab Results

Lyme disease with DICProvide antibiotics with supportive measures

Case Study 4 ndash Diagnosis

55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

Case Study 5 ndash Presentation

Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

Case Study 5 ndash Lab Results and Time Course

Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

TEST RESULT REFERENCE RANGE

Platelet count 33 x 109L 150-450 x 109L

PT 215 sec 103 ndash 128 sec

APTT 44 sec 26 ndash 36 sec

D-dimer 20 microgmL FEU lt025 microgml FEU

Fibrinogen 34 mgdL 200-375 mgdl

FII FV FVIII Low Not reported (NR)

FVII FIX FX vWF Normal NR

Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

(D) Illustration demonstrating repair

Case Study 5 ndash Diagnosis and Treatment

Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

Case Study 6 ndash Presentation

Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

Case Study 6 ndash Lab Results

Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

PT 63 sec gt control 113 ndash 146 sec

INR 658 1 ndash 125

APTT 80 sec gt control 25 ndash 34 sec

D-dimer gt200 microgmL DDU 02 microgmL DDU

Urine exam Proteinuria and hematuria 150-400 mgdl

Albumin 28 gdL NR

Hb 58 gdL NR

LDH 1196 UL NR

SGPT 144 IU NR

SGOT 88 IU NR

Bilirubin 32 mgdL NR

DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

day postop

Case Study 6 ndash Diagnosis and Treatment

Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

Case Study 6 ndash Discussion

Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

Case Study 7 ndash Presentation

Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

Case Study 7 ndash Presentation

Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

Case Study 7 ndash Lab Results vs Time

Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

Case Study 7 ndash Diagnosis and Treatment

Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

Case Study 7 ndash Diagnosis and Treatment

Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

DIC Take Home Messages

Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

DIC

Thank you Questions

  • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
  • Learning Objectives
  • Slide Number 3
  • Slide Number 4
  • Slide Number 5
  • Slide Number 6
  • Slide Number 7
  • Slide Number 8
  • Wound Sealing
  • The Three Steps of Hemostasis
  • Vessel Wall
  • Slide Number 12
  • Slide Number 13
  • Platelet Structure UnactivatedActivated
  • Primary Hemostasis
  • Primary Hemostasis Assays
  • Slide Number 17
  • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
  • Slide Number 19
  • Coagulation factors
  • Coagulation Assay Mechanisms
  • Slide Number 22
  • Fibrin Formation
  • Slide Number 24
  • Fibrinolysis Overview
  • Fibrinolysis Overview
  • Slide Number 27
  • Fibrinolysis Releases D-dimers
  • Basic Pathophysiology of DIC
  • Disseminated Intravascular Coagulation (DIC)
  • Purpura Fulminans with DIC Due to Meningococcal Sepsis
  • Clinical Conditions Associated With DIC
  • Frequency of DIC in Selected Disease States
  • Underlying Diseases in DIC Patients
  • Slide Number 36
  • Slide Number 37
  • Slide Number 38
  • Slide Number 39
  • Pathophysiology of DIC
  • Pathogenesis of DIC in Sepsis
  • Host Response in Severe Sepsis
  • Organ Failure in Severe Sepsis
  • Mechanism of DIC in Organ Failure
  • Interaction of Inflammation and Coagulation in Sepsis
  • Slide Number 47
  • Diverse and Opposing Effects of Thrombin
  • Coagulation and Fibrinolysis in DIC
  • Mechanism of DIC
  • Pathophysiology of DIC
  • Pathophysiology of DIC - Mechanism
  • Pathophysiology of DIC ndash 2 Types of Clinical pictures
  • Sub-Acute and Non-Overt DIC Clinical Findings
  • Pathophysiology of Overt DIC
  • Physiopathology of DIC ndash Overt DIC Findings
  • Slide Number 57
  • Slide Number 58
  • Slide Number 59
  • Slide Number 60
  • Slide Number 61
  • BREAK
  • Diagnostic and Management Approach for DIC
  • Diagnosis of DIC
  • Lab Diagnosis of DIC ndash Markers of Factor Consumption
  • Lab Diagnosis of DIC ndash Screening Tests
  • Slide Number 67
  • Slide Number 68
  • British Journal of Haematology Overt DIC Score
  • Slide Number 70
  • Slide Number 71
  • Slide Number 72
  • Slide Number 73
  • DIC Management Goals
  • DIC Management and Treatment
  • DIC Management Strategies
  • Anticoagulant Factor Concentrate Treatment
  • Anticoagulant Factor Concentrate Treatment Trials
  • Markers of Thrombin amp Plasmin Generation in DIC
  • D-dimer FDPs and DIC
  • D-Dimer and FDPs in DIC
  • Follow Up of DIC State of Disease
  • FMD-Dimer in DIC Major Differences
  • of Abnormal Results in Patients with Confirmed and Suspected DIC
  • Slide Number 85
  • Slide Number 86
  • Comparing an Automated FM vs Manual FSP Test
  • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
  • Diagnostic Performance of FM and D-dimer in DIC
  • Diagnostic Performance of FM and D-dimer in DIC
  • Diagnostic Performance of FM and D-dimer in DIC
  • Diagnostic Performance of FM and D-dimer in DIC
  • Diagnostic Performance of FM and D-dimer in DIC
  • Slide Number 94
  • Slide Number 95
  • Slide Number 96
  • Slide Number 97
  • Slide Number 98
  • Slide Number 99
  • DIC Case Studies
  • Case Study 1 - Presentation
  • Case Study 1 ndash Lab Results
  • Case Study 1 ndash Microscopy
  • Case Study 1 ndash Diagnosis and Therapy
  • Slide Number 105
  • Slide Number 106
  • Slide Number 107
  • Slide Number 108
  • Slide Number 109
  • Slide Number 110
  • Slide Number 111
  • Slide Number 112
  • Slide Number 113
  • Slide Number 114
  • Slide Number 115
  • Slide Number 116
  • Slide Number 117
  • Slide Number 118
  • Slide Number 119
  • Slide Number 120
  • Slide Number 121
  • Slide Number 122
  • Slide Number 123
  • Slide Number 124
  • Slide Number 125
  • DIC Take Home Messages
  • Slide Number 127
  • Slide Number 128

    Learning Objectives

    Describe the basic pathophysiology of DIC

    Demonstrate a diagnostic and management approach for DIC

    Compare markers of thrombin amp plasmin generation in DIC including D-Dimer fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs)

    Correlate DIC theory and testing to specific clinical cases

    DIC = Death is Coming

    What is Hemostasis

    Blood Circulation

    ARTERIES

    VEINS

    Occurs through blood vessels

    The heart pumps the blood

    Arteries carry oxygenated blood away from the heart under high pressure

    Veins carry de-oxygenated blood back to the heart under low pressure

    Hemostasis

    The mechanism that maintains blood fluidity

    Keeps a balance between bleeding and clotting

    2 major roles Stop bleeding by repairing holes in blood vessels Clean up the inside of blood vessels Removes temporary clot that stopped bleeding Sweeps off needless deposits that may cause blood flow

    blockages

    Bleeding =

    Hemorrhage

    Blood clot =

    Thrombosis

    Two Major Diseases Linked to Hemostatic Abnormalities

    Physiology of Hemostasis

    Wound Sealing

    EFFRACbreak in vessel

    FIBRINOLYSIS

    clot destruction

    PRIMARYHEMOSTASIS

    PLASMATICCOAGULATION

    strong clot

    wound sealing blood flow plusmn stopped

    The Three Steps of Hemostasis

    Primary Hemostasis Interaction between vessel wall platelets and adhesive proteins platelet clot

    Coagulation Consolidation of the platelet thrombus insoluble fibrin net

    bull Coagulation factors and inhibitors

    Fibrinolysis Clot lysis clot is digested

    bull Fibrinolytic activators and inhibitors

    Vessel Wall

    Intact endothelium non thrombogenic Synthesis of vasodilators (prostacyclin) No reaction either with platelets or factors

    Sub endotheliumTissue Endothelium

    blood

    When a vessel wall is damaged Exposure of the subendothelium Platelet adhesion Initiation of the mechanisms of coagulation and fibrinolysis

    PlateletsFactors

    Sub endotheliumTissue Endothelium

    blood

    Vessel Wall Damage

    Aim is to clog the damaged vessel ( asymp bricks without cement )

    Primary Hemostasis

    Platelet Structure UnactivatedActivated

    GpIb-IX-V

    GpIIb-IIIa

    α granules (raw materials)PF4 β-TG Fibrinogen VWF Factor V and PAI-1

    dense granules (energy and glue)ATP ADP SerotoninCa2+ Mg2+ P

    Hillman Robert S Ault Kenneth A Rinder Henry M Hematology in Clinical Practice 4th Edition McGraw-Hill New York NY 2005

    Primary Hemostasis

    2) activation2nd shape changeamp release

    platelet at rest 1) adhesion1st shape change

    3) aggregation(not reversible)

    Vasoconstriction occurs first

    Platelets then aggregate on the break in the vessel wall

    Primary Hemostasis AssaysRoutine Platelet count PT APTT TT

    Follow-up von Willebrand Factor Antigen determination Activity Factor VIII PFA-100 Platelet aggregation studies

    SpecializedSend Out Activation markers (b-TG PF4 GPV) Specialized tests for platelet function

    Aim is to strengthen the platelet plug

    Coagulation

    Coagulation is a balancebetween pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis

    THROMBIN

    Fibrinogen Fibrin

    bull Triggering agentsbull pro-enzyme enzyme (serine-protease FIIa FVIIa FIXa FXa)bull Cofactors (FVa amp FVIIIa)

    bull Serine-protease inhibitor Antithrombin (AT) bull Cofactorsinhibitors Protein C Sbull Tissue factor pathway inhibitor (TFPI)

    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

    Coagulation Cascade Schematic

    Coagulation factors

    Historic name

    Fibrinogen

    Prothrombin

    Proaccelerin

    Proconvertin

    Anti-hemophilic factor A

    Anti-hemophilic factor B

    Stuart factor

    Rosenthal factor

    Hageman factor

    Fibrin Stabilizing Factor

    Factor

    I

    II

    V

    VII

    VIII

    IX

    X

    XI

    XII

    XIII

    Function

    Substrate

    Pro-enzyme

    Pro-cofactor

    Pro-enzyme

    Pro-cofactor

    Pro-enzyme

    Pro-enzyme

    Pro-enzyme

    Pro-enzyme

    Pro-enzyme

    Pro-enzyme = Zymogen activation Active Enzyme

    Coagulation Assay Mechanisms

    aPTT Based

    PT Based

    PT Based

    Fibrin Under Microscope

    Weisel JW Structure of fibrin impact on clot stability J Thromb Haemost 2007 5 Suppl 1 116-24

    Low thrombin concentration

    High thrombin concentration

    Fibrin Formation

    Soluble FibrinPolymer

    ThrombinFibrinogen

    FM+ fibrinopeptides A amp B

    Stabilized Fibrin clot(not soluble)

    ThrombinXIII XIIIa

    (Digestion of Fibrin)

    Fibrinolysis

    Fibrinolysis Overview

    Destroys fibrin fibers

    Destroys the scab (dried wound)

    Maintains vessel integrity

    Fibrinolysis Overview

    Fibrin =cement fibers

    Plasmin

    Plasmin digests fibrin

    t-PA

    Pro Urokinase

    Urokinase

    PAI-1PAI-1

    Plasminogen Plasmin

    1st Step

    2nd Step

    Fibrinolysis Cascade

    t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin

    Extrinsic pathway(endothelia l cells)

    Intrinsic pathway(plasma)

    Fibrin clot

    D-dimerFibrin degradation products

    Fibrin

    TAFIa

    APAntiplasmin(amp a2-MG)

    PK Kallikrein

    XII

    Fibrinolysis Releases D-dimers

    D-dimer presence fibrin has been formed and digested in patients body

    Normal D-dimer level no thrombosis occurred in the patient

    Basic Pathophysiology of DIC

    Disseminated Intravascular Coagulation (DIC)

    Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management

    Clinical Manifestations of DICOrgan Ischemic Hemorrhagic

    Skin Pupura Fulminans Petechiae

    Gangrene Echymoses

    Acral cyanosis Oozing

    CNS Deliriumcoma Intracranial

    Infarcts Bleeding

    Renal OliguriaAzotemia Hematuria

    Cortical Necrosis

    Cardiovascular Myocardial dysfunction

    Pulmonary DyspneaHypoxia Hemorrhagic lung

    Infarct

    Gastrointestinal Ulcers infarcts Massive hemorrhage

    Endocrine Adrenal infarcts

    Purpura Fulminans with DIC Due to Meningococcal Sepsis

    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

    Clinical Conditions Associated With DIC

    Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

    Frequency of DIC in Selected Disease States

    Disease Frequency

    Gram-negative sepsis 30-50

    Severe trauma and systemic inflammation 50-70

    Metastasized tumors 15

    Abruptio placentaamniotic fluid embolism 50

    Severe preeclampsia 7

    Giant hemangioma 25

    Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

    Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017

    Underlying Diseases in DIC Patients

    In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively

    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

    Epidemiology of DIC

    Impact of DIC Status on Mortality - 1

    Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8

    Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC

    Impact of DIC Status on Mortality - 2

    Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

    Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients

    Impact of Age on Mortality in DIC Patients

    Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

    Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)

    Pathophysiology of DIC

    Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

    Pathogenesis of DIC in Sepsis

    Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15

    Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC

    Host Response in Severe Sepsis

    Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral

    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

    Organ Failure in Severe Sepsis

    Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure

    Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51

    Mechanism of DIC in Organ Failure

    Underlying condition(sepsis trauma)

    Cytokines

    TF-mediatedactivation of coagulation

    Depression of inhibitory systems

    Reducesfibrinolysis

    Fibrin deposition

    Organ failure

    Inadequate fibrin removal

    Fibrinformation

    Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )

    Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705

    Interaction of Inflammation and Coagulation in Sepsis

    Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines

    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

    Mechanism of Multiple Organ Failure in DIC

    Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

    Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

    lipopolysaccharides

    cytokines

    coagulation activation

    mononuclear cell

    tissue factor

    Diverse and Opposing Effects of Thrombin

    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

    Coagulation and Fibrinolysis in DIC

    Soluble fibrin Polymer

    XIIIa

    D-Dimer

    E

    Fibrin clot

    Fibrin Degradation Products

    Fibrinogen Thrombin

    Fibrinogen Degradation

    Products

    D E

    Plasmin

    DFM + fibrinopeptides

    Soluble FM ComplexesPre-throm

    boticPost-throm

    botic

    Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

    Mechanism of DIC

    THROMBOSIS

    Fibrin

    Blood activationEndothelial lysisTF expression

    BLEEDING

    FDPs

    D-Dimer

    Plasmin

    Pathophysiology of DIC

    1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

    thromboplastin influx of activated cells (monocytes macrophages)

    Results in an intravascular deposition of fibrin

    Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

    Second step Consumption and depletion of coagulation factors inhibitors (Protein C

    Protein S AT) and platelets Local fibrinolytic response

    bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

    FDP and D-Dimer

    Bleeding

    Pathophysiology of DIC - Mechanism

    Systemic activation of coagulation

    Intravasculardepositionof fibrin

    Thrombosis of small and midsize vessels

    and organ failure

    Depletion of platelets and

    coagulation factors

    Bleeding

    Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

    Pathophysiology of DIC ndash 2 Types of Clinical pictures

    Chronic = non - overt DICMay be unrecognized clinically

    Acute = overt DIClife threatening bleedingor multiple organ failure

    Sub-Acute and Non-Overt DIC Clinical Findings

    Compensated non-overt DIC Steady low level or intermittent activation

    bull Compensated by increased production of coagulation components and platelets

    Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

    Risk of decompensation leading to overt DIC

    Pathophysiology of Overt DIC

    Massive activation of coagulation and fibrinolysis

    Does not allow for compensatory efforts

    Rapid depletion of coagulation factors inhibitors and platelets

    Thrombosis multiple organ failures

    Bleeding complications and shock

    Physiopathology of DIC ndash Overt DIC Findings

    Thrombin generation

    Thrombosis

    Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

    Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

    Plasmin generationHemorrhage

    bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

    bull Tachycardia hypotension edema

    Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

    Pathogenesis Pathways in DIC

    Cytokines

    TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

    fibrin inadequateformation fibrin removal

    Fibrin deposition

    Inflammation

    Coagulation

    Stago Celebrates Lab Week 2017

    NA

    Stago 247 Educational Webinar Sites

    wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

    wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

    Stago Educational Apps

    HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

    iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

    BREAK

    Diagnostic and Management Approach for DIC

    Diagnosis of DIC

    Clinical diagnosis is obvious in cases of overt DIC

    Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

    Lab Diagnosis of DIC ndash Markers of Factor Consumption

    Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

    Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

    Important to recognize simultaneous formation of thrombin and plasmin

    Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

    Lab Diagnosis of DIC ndash Screening Tests

    Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

    Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

    fibrinogen level) repeat testing assesses progression

    Screening tests not clinically specific or sensitive for DIC

    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

    Laboratory Changes in Overt DIC

    DIC Diagnostic Practices Over Time

    Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

    British Journal of Haematology Overt DIC Score

    Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

    ISTH Step by Step DIC Algorithm

    Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

    US Based Validation of ISTH DIC Score

    When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

    Differential Diagnosis in DIC

    aHUS atypical hemolytic uremic syndrome

    HUS hemolytic uremic syndrome

    HIT heparin-induced thrombocytopenia

    ITP immune thrombocytopenic purpura

    TTP thrombotic thrombocytopenic purpura

    DIC and MAHA

    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

    lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

    When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

    DIC Management Goals

    Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

    Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

    DIC Management and Treatment

    Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

    Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

    requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

    Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

    DIC Management Strategies

    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

    Anticoagulant Factor Concentrate Treatment

    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

    Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

    Anticoagulant Factor Concentrate Treatment Trials

    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

    Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

    Markers of Thrombin amp Plasmin Generation in DIC

    D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

    Cut-off value

    Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

    degradation products Sensitive assay typically with cutoff adapted for DIC

    D-dimer FDPs and DIC

    D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

    Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

    Follow Up of DIC State of Disease

    Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

    Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

    FMD-Dimer in DIC Major Differences

    onset of thrombosis

    days

    Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

    FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

    D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

    of Abnormal Results in Patients with Confirmed and Suspected DIC

    0

    20

    40

    60

    80

    100

    94 85 90N = 62

    Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

    Positivity of Test Results ISTH Score and Disease State

    Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

    Red bar positive for 2 points of DIC score

    Pink bar positive for 1-2 points of DIC score

    HT hematopoietic tumor

    IF infection

    SC solid cancer

    Markers in Patients with or without DIC

    Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

    HT hematopoietic tumorIF infectionSC solid cancer

    Comparing an Automated FM vs Manual FSP Test

    Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

    Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

    Automated (Mitsubishi) vs Automated (Stago)

    In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

    Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

    Diagnostic Performance of FM and D-dimer in DIC

    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

    Diagnostic Performance of FM and D-dimer in DIC

    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

    In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

    Diagnostic Performance of FM and D-dimer in DIC

    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

    In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

    Diagnostic Performance of FM and D-dimer in DIC

    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

    In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

    Diagnostic Performance of FM and D-dimer in DIC

    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

    Diagnostic Performance of FM and D-dimer in DIC

    Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

    No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

    Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

    Diagnostic Performance of FM and D-dimer in DIC

    Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

    Non Overt DIC Overt DIC

    AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

    Trends in Markers of DIC for Different Patients

    Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

    Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

    Trends in Markers of DIC for Different Patients

    Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

    FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

    28 day outcome survival

    28 day outcome death

    Determination of Cutoffs of FM and D-dimer in DIC

    Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

    Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

    Determination of Cutoffs of FM and D-dimer in DIC

    Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

    Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

    DIC Case Studies

    Case Study 1 - Presentation

    18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

    Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

    WBC count 77 KμL 423 ndash 907 x KμL

    RBC count 17 MμL 137 ndash 175 x MμL

    Hemoglobin 67 gdL 137 ndash 175 gdL

    Hematocrit 195 401 ndash 510

    MCV 95 fL 790 ndash 922 fL

    MPV 12 fL 94 ndash 124 fL

    Platelet count 9 KμL 161 ndash 347 KμL

    Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

    Lymphocytes monocytes eosinophils basophils all below normal range

    PT 47 sec (corrected on mixing study) 116 ndash 152 sec

    APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

    Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

    D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

    Case Study 1 ndash Microscopy

    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

    Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

    Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

    DIC due to TF release by APL blasts

    Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

    Transfusions to replace factors along with platelets and RBCs during APL treatment

    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

    20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

    Case Study 2 ndash Presentation

    TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

    PT 30 sec 113 ndash 146 sec

    APTT 75 sec 25 ndash 34 sec

    D-dimer 078 microgml FEU lt050 microgml FEU

    Fibrinogen 92 mgdl 150-400 mgdl

    pH 728 738 to 742

    PaO2 570 mmHg 80-100 mmHg

    WBC 33 times 103mm3 40-11 times 103mm3

    ALT 111 IUL 0ndash34 IUL

    AST 61 IUL 0ndash34 IUL

    BUN 303 mgdL 08-13 mgdL

    Case Study 2 ndash Lab Results

    Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

    Case Study 2 ndash Diagnosis

    60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

    Case Study 3 ndash Presentation

    TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

    PT 228 sec 113 ndash 146 sec

    APTT 45 sec 25 ndash 34 sec

    D-dimer 080 microgml FEU lt050 microgmL FEU

    Fibrinogen 82 mgdL 150-400 mgdL

    FV Normal 70-120

    FVII Normal 55-170

    FVIII Normal 60-150

    Protein C Normal 70-130

    Hb 134 gdL 14-16 gdL

    WBC 81 times 103mm3 40-11 times 103mm3

    ALT 32 IUL 0ndash34 IUL

    AST 28 IUL 0ndash34 IUL

    BUN 09 mgdL 08-13 mgdL

    Case Study 3 ndash Lab Results

    Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

    Case Study 3 ndash Diagnosis and Therapy

    Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

    Case Study 4 ndash Presentation

    TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

    PT 28 sec 113 ndash 146 sec

    APTT 71 sec 25 ndash 34 sec

    D-dimer 31 microgmL FEU lt050 microgml FEU

    Fibrinogen 92 mgdL 150-400 mgdl

    FV Normal 70-120

    FVII Normal 55-170

    FVIII Normal 60-150

    Protein C Normal 70-130

    Hb 158 gdL 14-16 gdL

    WBC 71 times 103mm3 40-11 times 103mm3

    ALT 60 IUL 0ndash34 IUL

    AST 47 IUL 0ndash34 IUL

    BUN 38 mgdL 08-13 mgdL

    Case Study 4 ndash Lab Results

    Lyme disease with DICProvide antibiotics with supportive measures

    Case Study 4 ndash Diagnosis

    55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

    Case Study 5 ndash Presentation

    Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

    Case Study 5 ndash Lab Results and Time Course

    Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

    TEST RESULT REFERENCE RANGE

    Platelet count 33 x 109L 150-450 x 109L

    PT 215 sec 103 ndash 128 sec

    APTT 44 sec 26 ndash 36 sec

    D-dimer 20 microgmL FEU lt025 microgml FEU

    Fibrinogen 34 mgdL 200-375 mgdl

    FII FV FVIII Low Not reported (NR)

    FVII FIX FX vWF Normal NR

    Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

    DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

    dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

    (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

    (D) Illustration demonstrating repair

    Case Study 5 ndash Diagnosis and Treatment

    Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

    29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

    Case Study 6 ndash Presentation

    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

    Case Study 6 ndash Lab Results

    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

    TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

    PT 63 sec gt control 113 ndash 146 sec

    INR 658 1 ndash 125

    APTT 80 sec gt control 25 ndash 34 sec

    D-dimer gt200 microgmL DDU 02 microgmL DDU

    Urine exam Proteinuria and hematuria 150-400 mgdl

    Albumin 28 gdL NR

    Hb 58 gdL NR

    LDH 1196 UL NR

    SGPT 144 IU NR

    SGOT 88 IU NR

    Bilirubin 32 mgdL NR

    DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

    day postop

    Case Study 6 ndash Diagnosis and Treatment

    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

    HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

    Case Study 6 ndash Discussion

    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

    44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

    Case Study 7 ndash Presentation

    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

    On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

    Case Study 7 ndash Presentation

    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

    Case Study 7 ndash Lab Results vs Time

    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

    Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

    Case Study 7 ndash Diagnosis and Treatment

    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

    On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

    Case Study 7 ndash Diagnosis and Treatment

    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

    DIC Take Home Messages

    Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

    Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

    DIC

    Thank you Questions

    • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
    • Learning Objectives
    • Slide Number 3
    • Slide Number 4
    • Slide Number 5
    • Slide Number 6
    • Slide Number 7
    • Slide Number 8
    • Wound Sealing
    • The Three Steps of Hemostasis
    • Vessel Wall
    • Slide Number 12
    • Slide Number 13
    • Platelet Structure UnactivatedActivated
    • Primary Hemostasis
    • Primary Hemostasis Assays
    • Slide Number 17
    • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
    • Slide Number 19
    • Coagulation factors
    • Coagulation Assay Mechanisms
    • Slide Number 22
    • Fibrin Formation
    • Slide Number 24
    • Fibrinolysis Overview
    • Fibrinolysis Overview
    • Slide Number 27
    • Fibrinolysis Releases D-dimers
    • Basic Pathophysiology of DIC
    • Disseminated Intravascular Coagulation (DIC)
    • Purpura Fulminans with DIC Due to Meningococcal Sepsis
    • Clinical Conditions Associated With DIC
    • Frequency of DIC in Selected Disease States
    • Underlying Diseases in DIC Patients
    • Slide Number 36
    • Slide Number 37
    • Slide Number 38
    • Slide Number 39
    • Pathophysiology of DIC
    • Pathogenesis of DIC in Sepsis
    • Host Response in Severe Sepsis
    • Organ Failure in Severe Sepsis
    • Mechanism of DIC in Organ Failure
    • Interaction of Inflammation and Coagulation in Sepsis
    • Slide Number 47
    • Diverse and Opposing Effects of Thrombin
    • Coagulation and Fibrinolysis in DIC
    • Mechanism of DIC
    • Pathophysiology of DIC
    • Pathophysiology of DIC - Mechanism
    • Pathophysiology of DIC ndash 2 Types of Clinical pictures
    • Sub-Acute and Non-Overt DIC Clinical Findings
    • Pathophysiology of Overt DIC
    • Physiopathology of DIC ndash Overt DIC Findings
    • Slide Number 57
    • Slide Number 58
    • Slide Number 59
    • Slide Number 60
    • Slide Number 61
    • BREAK
    • Diagnostic and Management Approach for DIC
    • Diagnosis of DIC
    • Lab Diagnosis of DIC ndash Markers of Factor Consumption
    • Lab Diagnosis of DIC ndash Screening Tests
    • Slide Number 67
    • Slide Number 68
    • British Journal of Haematology Overt DIC Score
    • Slide Number 70
    • Slide Number 71
    • Slide Number 72
    • Slide Number 73
    • DIC Management Goals
    • DIC Management and Treatment
    • DIC Management Strategies
    • Anticoagulant Factor Concentrate Treatment
    • Anticoagulant Factor Concentrate Treatment Trials
    • Markers of Thrombin amp Plasmin Generation in DIC
    • D-dimer FDPs and DIC
    • D-Dimer and FDPs in DIC
    • Follow Up of DIC State of Disease
    • FMD-Dimer in DIC Major Differences
    • of Abnormal Results in Patients with Confirmed and Suspected DIC
    • Slide Number 85
    • Slide Number 86
    • Comparing an Automated FM vs Manual FSP Test
    • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
    • Diagnostic Performance of FM and D-dimer in DIC
    • Diagnostic Performance of FM and D-dimer in DIC
    • Diagnostic Performance of FM and D-dimer in DIC
    • Diagnostic Performance of FM and D-dimer in DIC
    • Diagnostic Performance of FM and D-dimer in DIC
    • Slide Number 94
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    • DIC Case Studies
    • Case Study 1 - Presentation
    • Case Study 1 ndash Lab Results
    • Case Study 1 ndash Microscopy
    • Case Study 1 ndash Diagnosis and Therapy
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    • DIC Take Home Messages
    • Slide Number 127
    • Slide Number 128

      DIC = Death is Coming

      What is Hemostasis

      Blood Circulation

      ARTERIES

      VEINS

      Occurs through blood vessels

      The heart pumps the blood

      Arteries carry oxygenated blood away from the heart under high pressure

      Veins carry de-oxygenated blood back to the heart under low pressure

      Hemostasis

      The mechanism that maintains blood fluidity

      Keeps a balance between bleeding and clotting

      2 major roles Stop bleeding by repairing holes in blood vessels Clean up the inside of blood vessels Removes temporary clot that stopped bleeding Sweeps off needless deposits that may cause blood flow

      blockages

      Bleeding =

      Hemorrhage

      Blood clot =

      Thrombosis

      Two Major Diseases Linked to Hemostatic Abnormalities

      Physiology of Hemostasis

      Wound Sealing

      EFFRACbreak in vessel

      FIBRINOLYSIS

      clot destruction

      PRIMARYHEMOSTASIS

      PLASMATICCOAGULATION

      strong clot

      wound sealing blood flow plusmn stopped

      The Three Steps of Hemostasis

      Primary Hemostasis Interaction between vessel wall platelets and adhesive proteins platelet clot

      Coagulation Consolidation of the platelet thrombus insoluble fibrin net

      bull Coagulation factors and inhibitors

      Fibrinolysis Clot lysis clot is digested

      bull Fibrinolytic activators and inhibitors

      Vessel Wall

      Intact endothelium non thrombogenic Synthesis of vasodilators (prostacyclin) No reaction either with platelets or factors

      Sub endotheliumTissue Endothelium

      blood

      When a vessel wall is damaged Exposure of the subendothelium Platelet adhesion Initiation of the mechanisms of coagulation and fibrinolysis

      PlateletsFactors

      Sub endotheliumTissue Endothelium

      blood

      Vessel Wall Damage

      Aim is to clog the damaged vessel ( asymp bricks without cement )

      Primary Hemostasis

      Platelet Structure UnactivatedActivated

      GpIb-IX-V

      GpIIb-IIIa

      α granules (raw materials)PF4 β-TG Fibrinogen VWF Factor V and PAI-1

      dense granules (energy and glue)ATP ADP SerotoninCa2+ Mg2+ P

      Hillman Robert S Ault Kenneth A Rinder Henry M Hematology in Clinical Practice 4th Edition McGraw-Hill New York NY 2005

      Primary Hemostasis

      2) activation2nd shape changeamp release

      platelet at rest 1) adhesion1st shape change

      3) aggregation(not reversible)

      Vasoconstriction occurs first

      Platelets then aggregate on the break in the vessel wall

      Primary Hemostasis AssaysRoutine Platelet count PT APTT TT

      Follow-up von Willebrand Factor Antigen determination Activity Factor VIII PFA-100 Platelet aggregation studies

      SpecializedSend Out Activation markers (b-TG PF4 GPV) Specialized tests for platelet function

      Aim is to strengthen the platelet plug

      Coagulation

      Coagulation is a balancebetween pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis

      THROMBIN

      Fibrinogen Fibrin

      bull Triggering agentsbull pro-enzyme enzyme (serine-protease FIIa FVIIa FIXa FXa)bull Cofactors (FVa amp FVIIIa)

      bull Serine-protease inhibitor Antithrombin (AT) bull Cofactorsinhibitors Protein C Sbull Tissue factor pathway inhibitor (TFPI)

      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

      Coagulation Cascade Schematic

      Coagulation factors

      Historic name

      Fibrinogen

      Prothrombin

      Proaccelerin

      Proconvertin

      Anti-hemophilic factor A

      Anti-hemophilic factor B

      Stuart factor

      Rosenthal factor

      Hageman factor

      Fibrin Stabilizing Factor

      Factor

      I

      II

      V

      VII

      VIII

      IX

      X

      XI

      XII

      XIII

      Function

      Substrate

      Pro-enzyme

      Pro-cofactor

      Pro-enzyme

      Pro-cofactor

      Pro-enzyme

      Pro-enzyme

      Pro-enzyme

      Pro-enzyme

      Pro-enzyme

      Pro-enzyme = Zymogen activation Active Enzyme

      Coagulation Assay Mechanisms

      aPTT Based

      PT Based

      PT Based

      Fibrin Under Microscope

      Weisel JW Structure of fibrin impact on clot stability J Thromb Haemost 2007 5 Suppl 1 116-24

      Low thrombin concentration

      High thrombin concentration

      Fibrin Formation

      Soluble FibrinPolymer

      ThrombinFibrinogen

      FM+ fibrinopeptides A amp B

      Stabilized Fibrin clot(not soluble)

      ThrombinXIII XIIIa

      (Digestion of Fibrin)

      Fibrinolysis

      Fibrinolysis Overview

      Destroys fibrin fibers

      Destroys the scab (dried wound)

      Maintains vessel integrity

      Fibrinolysis Overview

      Fibrin =cement fibers

      Plasmin

      Plasmin digests fibrin

      t-PA

      Pro Urokinase

      Urokinase

      PAI-1PAI-1

      Plasminogen Plasmin

      1st Step

      2nd Step

      Fibrinolysis Cascade

      t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin

      Extrinsic pathway(endothelia l cells)

      Intrinsic pathway(plasma)

      Fibrin clot

      D-dimerFibrin degradation products

      Fibrin

      TAFIa

      APAntiplasmin(amp a2-MG)

      PK Kallikrein

      XII

      Fibrinolysis Releases D-dimers

      D-dimer presence fibrin has been formed and digested in patients body

      Normal D-dimer level no thrombosis occurred in the patient

      Basic Pathophysiology of DIC

      Disseminated Intravascular Coagulation (DIC)

      Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management

      Clinical Manifestations of DICOrgan Ischemic Hemorrhagic

      Skin Pupura Fulminans Petechiae

      Gangrene Echymoses

      Acral cyanosis Oozing

      CNS Deliriumcoma Intracranial

      Infarcts Bleeding

      Renal OliguriaAzotemia Hematuria

      Cortical Necrosis

      Cardiovascular Myocardial dysfunction

      Pulmonary DyspneaHypoxia Hemorrhagic lung

      Infarct

      Gastrointestinal Ulcers infarcts Massive hemorrhage

      Endocrine Adrenal infarcts

      Purpura Fulminans with DIC Due to Meningococcal Sepsis

      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

      Clinical Conditions Associated With DIC

      Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

      Frequency of DIC in Selected Disease States

      Disease Frequency

      Gram-negative sepsis 30-50

      Severe trauma and systemic inflammation 50-70

      Metastasized tumors 15

      Abruptio placentaamniotic fluid embolism 50

      Severe preeclampsia 7

      Giant hemangioma 25

      Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

      Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017

      Underlying Diseases in DIC Patients

      In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively

      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

      Epidemiology of DIC

      Impact of DIC Status on Mortality - 1

      Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8

      Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC

      Impact of DIC Status on Mortality - 2

      Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

      Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients

      Impact of Age on Mortality in DIC Patients

      Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

      Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)

      Pathophysiology of DIC

      Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

      Pathogenesis of DIC in Sepsis

      Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15

      Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC

      Host Response in Severe Sepsis

      Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral

      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

      Organ Failure in Severe Sepsis

      Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure

      Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51

      Mechanism of DIC in Organ Failure

      Underlying condition(sepsis trauma)

      Cytokines

      TF-mediatedactivation of coagulation

      Depression of inhibitory systems

      Reducesfibrinolysis

      Fibrin deposition

      Organ failure

      Inadequate fibrin removal

      Fibrinformation

      Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )

      Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705

      Interaction of Inflammation and Coagulation in Sepsis

      Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines

      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

      Mechanism of Multiple Organ Failure in DIC

      Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

      Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

      lipopolysaccharides

      cytokines

      coagulation activation

      mononuclear cell

      tissue factor

      Diverse and Opposing Effects of Thrombin

      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

      Coagulation and Fibrinolysis in DIC

      Soluble fibrin Polymer

      XIIIa

      D-Dimer

      E

      Fibrin clot

      Fibrin Degradation Products

      Fibrinogen Thrombin

      Fibrinogen Degradation

      Products

      D E

      Plasmin

      DFM + fibrinopeptides

      Soluble FM ComplexesPre-throm

      boticPost-throm

      botic

      Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

      Mechanism of DIC

      THROMBOSIS

      Fibrin

      Blood activationEndothelial lysisTF expression

      BLEEDING

      FDPs

      D-Dimer

      Plasmin

      Pathophysiology of DIC

      1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

      thromboplastin influx of activated cells (monocytes macrophages)

      Results in an intravascular deposition of fibrin

      Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

      Second step Consumption and depletion of coagulation factors inhibitors (Protein C

      Protein S AT) and platelets Local fibrinolytic response

      bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

      FDP and D-Dimer

      Bleeding

      Pathophysiology of DIC - Mechanism

      Systemic activation of coagulation

      Intravasculardepositionof fibrin

      Thrombosis of small and midsize vessels

      and organ failure

      Depletion of platelets and

      coagulation factors

      Bleeding

      Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

      Pathophysiology of DIC ndash 2 Types of Clinical pictures

      Chronic = non - overt DICMay be unrecognized clinically

      Acute = overt DIClife threatening bleedingor multiple organ failure

      Sub-Acute and Non-Overt DIC Clinical Findings

      Compensated non-overt DIC Steady low level or intermittent activation

      bull Compensated by increased production of coagulation components and platelets

      Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

      Risk of decompensation leading to overt DIC

      Pathophysiology of Overt DIC

      Massive activation of coagulation and fibrinolysis

      Does not allow for compensatory efforts

      Rapid depletion of coagulation factors inhibitors and platelets

      Thrombosis multiple organ failures

      Bleeding complications and shock

      Physiopathology of DIC ndash Overt DIC Findings

      Thrombin generation

      Thrombosis

      Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

      Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

      Plasmin generationHemorrhage

      bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

      bull Tachycardia hypotension edema

      Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

      Pathogenesis Pathways in DIC

      Cytokines

      TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

      fibrin inadequateformation fibrin removal

      Fibrin deposition

      Inflammation

      Coagulation

      Stago Celebrates Lab Week 2017

      NA

      Stago 247 Educational Webinar Sites

      wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

      wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

      Stago Educational Apps

      HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

      iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

      BREAK

      Diagnostic and Management Approach for DIC

      Diagnosis of DIC

      Clinical diagnosis is obvious in cases of overt DIC

      Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

      Lab Diagnosis of DIC ndash Markers of Factor Consumption

      Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

      Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

      Important to recognize simultaneous formation of thrombin and plasmin

      Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

      Lab Diagnosis of DIC ndash Screening Tests

      Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

      Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

      fibrinogen level) repeat testing assesses progression

      Screening tests not clinically specific or sensitive for DIC

      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

      Laboratory Changes in Overt DIC

      DIC Diagnostic Practices Over Time

      Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

      British Journal of Haematology Overt DIC Score

      Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

      ISTH Step by Step DIC Algorithm

      Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

      US Based Validation of ISTH DIC Score

      When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

      Differential Diagnosis in DIC

      aHUS atypical hemolytic uremic syndrome

      HUS hemolytic uremic syndrome

      HIT heparin-induced thrombocytopenia

      ITP immune thrombocytopenic purpura

      TTP thrombotic thrombocytopenic purpura

      DIC and MAHA

      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

      lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

      When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

      DIC Management Goals

      Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

      Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

      DIC Management and Treatment

      Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

      Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

      requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

      Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

      DIC Management Strategies

      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

      Anticoagulant Factor Concentrate Treatment

      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

      Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

      Anticoagulant Factor Concentrate Treatment Trials

      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

      Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

      Markers of Thrombin amp Plasmin Generation in DIC

      D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

      Cut-off value

      Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

      degradation products Sensitive assay typically with cutoff adapted for DIC

      D-dimer FDPs and DIC

      D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

      Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

      Follow Up of DIC State of Disease

      Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

      Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

      FMD-Dimer in DIC Major Differences

      onset of thrombosis

      days

      Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

      FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

      D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

      of Abnormal Results in Patients with Confirmed and Suspected DIC

      0

      20

      40

      60

      80

      100

      94 85 90N = 62

      Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

      Positivity of Test Results ISTH Score and Disease State

      Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

      Red bar positive for 2 points of DIC score

      Pink bar positive for 1-2 points of DIC score

      HT hematopoietic tumor

      IF infection

      SC solid cancer

      Markers in Patients with or without DIC

      Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

      HT hematopoietic tumorIF infectionSC solid cancer

      Comparing an Automated FM vs Manual FSP Test

      Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

      Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

      Automated (Mitsubishi) vs Automated (Stago)

      In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

      Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

      Diagnostic Performance of FM and D-dimer in DIC

      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

      Diagnostic Performance of FM and D-dimer in DIC

      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

      In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

      Diagnostic Performance of FM and D-dimer in DIC

      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

      In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

      Diagnostic Performance of FM and D-dimer in DIC

      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

      In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

      Diagnostic Performance of FM and D-dimer in DIC

      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

      Diagnostic Performance of FM and D-dimer in DIC

      Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

      No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

      Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

      Diagnostic Performance of FM and D-dimer in DIC

      Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

      Non Overt DIC Overt DIC

      AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

      Trends in Markers of DIC for Different Patients

      Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

      Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

      Trends in Markers of DIC for Different Patients

      Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

      FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

      28 day outcome survival

      28 day outcome death

      Determination of Cutoffs of FM and D-dimer in DIC

      Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

      Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

      Determination of Cutoffs of FM and D-dimer in DIC

      Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

      Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

      DIC Case Studies

      Case Study 1 - Presentation

      18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

      Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

      WBC count 77 KμL 423 ndash 907 x KμL

      RBC count 17 MμL 137 ndash 175 x MμL

      Hemoglobin 67 gdL 137 ndash 175 gdL

      Hematocrit 195 401 ndash 510

      MCV 95 fL 790 ndash 922 fL

      MPV 12 fL 94 ndash 124 fL

      Platelet count 9 KμL 161 ndash 347 KμL

      Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

      Lymphocytes monocytes eosinophils basophils all below normal range

      PT 47 sec (corrected on mixing study) 116 ndash 152 sec

      APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

      Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

      D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

      Case Study 1 ndash Microscopy

      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

      Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

      Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

      DIC due to TF release by APL blasts

      Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

      Transfusions to replace factors along with platelets and RBCs during APL treatment

      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

      20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

      Case Study 2 ndash Presentation

      TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

      PT 30 sec 113 ndash 146 sec

      APTT 75 sec 25 ndash 34 sec

      D-dimer 078 microgml FEU lt050 microgml FEU

      Fibrinogen 92 mgdl 150-400 mgdl

      pH 728 738 to 742

      PaO2 570 mmHg 80-100 mmHg

      WBC 33 times 103mm3 40-11 times 103mm3

      ALT 111 IUL 0ndash34 IUL

      AST 61 IUL 0ndash34 IUL

      BUN 303 mgdL 08-13 mgdL

      Case Study 2 ndash Lab Results

      Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

      Case Study 2 ndash Diagnosis

      60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

      Case Study 3 ndash Presentation

      TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

      PT 228 sec 113 ndash 146 sec

      APTT 45 sec 25 ndash 34 sec

      D-dimer 080 microgml FEU lt050 microgmL FEU

      Fibrinogen 82 mgdL 150-400 mgdL

      FV Normal 70-120

      FVII Normal 55-170

      FVIII Normal 60-150

      Protein C Normal 70-130

      Hb 134 gdL 14-16 gdL

      WBC 81 times 103mm3 40-11 times 103mm3

      ALT 32 IUL 0ndash34 IUL

      AST 28 IUL 0ndash34 IUL

      BUN 09 mgdL 08-13 mgdL

      Case Study 3 ndash Lab Results

      Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

      Case Study 3 ndash Diagnosis and Therapy

      Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

      Case Study 4 ndash Presentation

      TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

      PT 28 sec 113 ndash 146 sec

      APTT 71 sec 25 ndash 34 sec

      D-dimer 31 microgmL FEU lt050 microgml FEU

      Fibrinogen 92 mgdL 150-400 mgdl

      FV Normal 70-120

      FVII Normal 55-170

      FVIII Normal 60-150

      Protein C Normal 70-130

      Hb 158 gdL 14-16 gdL

      WBC 71 times 103mm3 40-11 times 103mm3

      ALT 60 IUL 0ndash34 IUL

      AST 47 IUL 0ndash34 IUL

      BUN 38 mgdL 08-13 mgdL

      Case Study 4 ndash Lab Results

      Lyme disease with DICProvide antibiotics with supportive measures

      Case Study 4 ndash Diagnosis

      55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

      Case Study 5 ndash Presentation

      Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

      Case Study 5 ndash Lab Results and Time Course

      Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

      TEST RESULT REFERENCE RANGE

      Platelet count 33 x 109L 150-450 x 109L

      PT 215 sec 103 ndash 128 sec

      APTT 44 sec 26 ndash 36 sec

      D-dimer 20 microgmL FEU lt025 microgml FEU

      Fibrinogen 34 mgdL 200-375 mgdl

      FII FV FVIII Low Not reported (NR)

      FVII FIX FX vWF Normal NR

      Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

      DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

      dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

      (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

      (D) Illustration demonstrating repair

      Case Study 5 ndash Diagnosis and Treatment

      Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

      29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

      Case Study 6 ndash Presentation

      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

      Case Study 6 ndash Lab Results

      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

      TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

      PT 63 sec gt control 113 ndash 146 sec

      INR 658 1 ndash 125

      APTT 80 sec gt control 25 ndash 34 sec

      D-dimer gt200 microgmL DDU 02 microgmL DDU

      Urine exam Proteinuria and hematuria 150-400 mgdl

      Albumin 28 gdL NR

      Hb 58 gdL NR

      LDH 1196 UL NR

      SGPT 144 IU NR

      SGOT 88 IU NR

      Bilirubin 32 mgdL NR

      DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

      day postop

      Case Study 6 ndash Diagnosis and Treatment

      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

      HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

      Case Study 6 ndash Discussion

      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

      44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

      Case Study 7 ndash Presentation

      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

      On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

      Case Study 7 ndash Presentation

      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

      Case Study 7 ndash Lab Results vs Time

      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

      Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

      Case Study 7 ndash Diagnosis and Treatment

      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

      On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

      Case Study 7 ndash Diagnosis and Treatment

      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

      DIC Take Home Messages

      Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

      Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

      DIC

      Thank you Questions

      • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
      • Learning Objectives
      • Slide Number 3
      • Slide Number 4
      • Slide Number 5
      • Slide Number 6
      • Slide Number 7
      • Slide Number 8
      • Wound Sealing
      • The Three Steps of Hemostasis
      • Vessel Wall
      • Slide Number 12
      • Slide Number 13
      • Platelet Structure UnactivatedActivated
      • Primary Hemostasis
      • Primary Hemostasis Assays
      • Slide Number 17
      • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
      • Slide Number 19
      • Coagulation factors
      • Coagulation Assay Mechanisms
      • Slide Number 22
      • Fibrin Formation
      • Slide Number 24
      • Fibrinolysis Overview
      • Fibrinolysis Overview
      • Slide Number 27
      • Fibrinolysis Releases D-dimers
      • Basic Pathophysiology of DIC
      • Disseminated Intravascular Coagulation (DIC)
      • Purpura Fulminans with DIC Due to Meningococcal Sepsis
      • Clinical Conditions Associated With DIC
      • Frequency of DIC in Selected Disease States
      • Underlying Diseases in DIC Patients
      • Slide Number 36
      • Slide Number 37
      • Slide Number 38
      • Slide Number 39
      • Pathophysiology of DIC
      • Pathogenesis of DIC in Sepsis
      • Host Response in Severe Sepsis
      • Organ Failure in Severe Sepsis
      • Mechanism of DIC in Organ Failure
      • Interaction of Inflammation and Coagulation in Sepsis
      • Slide Number 47
      • Diverse and Opposing Effects of Thrombin
      • Coagulation and Fibrinolysis in DIC
      • Mechanism of DIC
      • Pathophysiology of DIC
      • Pathophysiology of DIC - Mechanism
      • Pathophysiology of DIC ndash 2 Types of Clinical pictures
      • Sub-Acute and Non-Overt DIC Clinical Findings
      • Pathophysiology of Overt DIC
      • Physiopathology of DIC ndash Overt DIC Findings
      • Slide Number 57
      • Slide Number 58
      • Slide Number 59
      • Slide Number 60
      • Slide Number 61
      • BREAK
      • Diagnostic and Management Approach for DIC
      • Diagnosis of DIC
      • Lab Diagnosis of DIC ndash Markers of Factor Consumption
      • Lab Diagnosis of DIC ndash Screening Tests
      • Slide Number 67
      • Slide Number 68
      • British Journal of Haematology Overt DIC Score
      • Slide Number 70
      • Slide Number 71
      • Slide Number 72
      • Slide Number 73
      • DIC Management Goals
      • DIC Management and Treatment
      • DIC Management Strategies
      • Anticoagulant Factor Concentrate Treatment
      • Anticoagulant Factor Concentrate Treatment Trials
      • Markers of Thrombin amp Plasmin Generation in DIC
      • D-dimer FDPs and DIC
      • D-Dimer and FDPs in DIC
      • Follow Up of DIC State of Disease
      • FMD-Dimer in DIC Major Differences
      • of Abnormal Results in Patients with Confirmed and Suspected DIC
      • Slide Number 85
      • Slide Number 86
      • Comparing an Automated FM vs Manual FSP Test
      • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
      • Diagnostic Performance of FM and D-dimer in DIC
      • Diagnostic Performance of FM and D-dimer in DIC
      • Diagnostic Performance of FM and D-dimer in DIC
      • Diagnostic Performance of FM and D-dimer in DIC
      • Diagnostic Performance of FM and D-dimer in DIC
      • Slide Number 94
      • Slide Number 95
      • Slide Number 96
      • Slide Number 97
      • Slide Number 98
      • Slide Number 99
      • DIC Case Studies
      • Case Study 1 - Presentation
      • Case Study 1 ndash Lab Results
      • Case Study 1 ndash Microscopy
      • Case Study 1 ndash Diagnosis and Therapy
      • Slide Number 105
      • Slide Number 106
      • Slide Number 107
      • Slide Number 108
      • Slide Number 109
      • Slide Number 110
      • Slide Number 111
      • Slide Number 112
      • Slide Number 113
      • Slide Number 114
      • Slide Number 115
      • Slide Number 116
      • Slide Number 117
      • Slide Number 118
      • Slide Number 119
      • Slide Number 120
      • Slide Number 121
      • Slide Number 122
      • Slide Number 123
      • Slide Number 124
      • Slide Number 125
      • DIC Take Home Messages
      • Slide Number 127
      • Slide Number 128

        What is Hemostasis

        Blood Circulation

        ARTERIES

        VEINS

        Occurs through blood vessels

        The heart pumps the blood

        Arteries carry oxygenated blood away from the heart under high pressure

        Veins carry de-oxygenated blood back to the heart under low pressure

        Hemostasis

        The mechanism that maintains blood fluidity

        Keeps a balance between bleeding and clotting

        2 major roles Stop bleeding by repairing holes in blood vessels Clean up the inside of blood vessels Removes temporary clot that stopped bleeding Sweeps off needless deposits that may cause blood flow

        blockages

        Bleeding =

        Hemorrhage

        Blood clot =

        Thrombosis

        Two Major Diseases Linked to Hemostatic Abnormalities

        Physiology of Hemostasis

        Wound Sealing

        EFFRACbreak in vessel

        FIBRINOLYSIS

        clot destruction

        PRIMARYHEMOSTASIS

        PLASMATICCOAGULATION

        strong clot

        wound sealing blood flow plusmn stopped

        The Three Steps of Hemostasis

        Primary Hemostasis Interaction between vessel wall platelets and adhesive proteins platelet clot

        Coagulation Consolidation of the platelet thrombus insoluble fibrin net

        bull Coagulation factors and inhibitors

        Fibrinolysis Clot lysis clot is digested

        bull Fibrinolytic activators and inhibitors

        Vessel Wall

        Intact endothelium non thrombogenic Synthesis of vasodilators (prostacyclin) No reaction either with platelets or factors

        Sub endotheliumTissue Endothelium

        blood

        When a vessel wall is damaged Exposure of the subendothelium Platelet adhesion Initiation of the mechanisms of coagulation and fibrinolysis

        PlateletsFactors

        Sub endotheliumTissue Endothelium

        blood

        Vessel Wall Damage

        Aim is to clog the damaged vessel ( asymp bricks without cement )

        Primary Hemostasis

        Platelet Structure UnactivatedActivated

        GpIb-IX-V

        GpIIb-IIIa

        α granules (raw materials)PF4 β-TG Fibrinogen VWF Factor V and PAI-1

        dense granules (energy and glue)ATP ADP SerotoninCa2+ Mg2+ P

        Hillman Robert S Ault Kenneth A Rinder Henry M Hematology in Clinical Practice 4th Edition McGraw-Hill New York NY 2005

        Primary Hemostasis

        2) activation2nd shape changeamp release

        platelet at rest 1) adhesion1st shape change

        3) aggregation(not reversible)

        Vasoconstriction occurs first

        Platelets then aggregate on the break in the vessel wall

        Primary Hemostasis AssaysRoutine Platelet count PT APTT TT

        Follow-up von Willebrand Factor Antigen determination Activity Factor VIII PFA-100 Platelet aggregation studies

        SpecializedSend Out Activation markers (b-TG PF4 GPV) Specialized tests for platelet function

        Aim is to strengthen the platelet plug

        Coagulation

        Coagulation is a balancebetween pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis

        THROMBIN

        Fibrinogen Fibrin

        bull Triggering agentsbull pro-enzyme enzyme (serine-protease FIIa FVIIa FIXa FXa)bull Cofactors (FVa amp FVIIIa)

        bull Serine-protease inhibitor Antithrombin (AT) bull Cofactorsinhibitors Protein C Sbull Tissue factor pathway inhibitor (TFPI)

        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

        Coagulation Cascade Schematic

        Coagulation factors

        Historic name

        Fibrinogen

        Prothrombin

        Proaccelerin

        Proconvertin

        Anti-hemophilic factor A

        Anti-hemophilic factor B

        Stuart factor

        Rosenthal factor

        Hageman factor

        Fibrin Stabilizing Factor

        Factor

        I

        II

        V

        VII

        VIII

        IX

        X

        XI

        XII

        XIII

        Function

        Substrate

        Pro-enzyme

        Pro-cofactor

        Pro-enzyme

        Pro-cofactor

        Pro-enzyme

        Pro-enzyme

        Pro-enzyme

        Pro-enzyme

        Pro-enzyme

        Pro-enzyme = Zymogen activation Active Enzyme

        Coagulation Assay Mechanisms

        aPTT Based

        PT Based

        PT Based

        Fibrin Under Microscope

        Weisel JW Structure of fibrin impact on clot stability J Thromb Haemost 2007 5 Suppl 1 116-24

        Low thrombin concentration

        High thrombin concentration

        Fibrin Formation

        Soluble FibrinPolymer

        ThrombinFibrinogen

        FM+ fibrinopeptides A amp B

        Stabilized Fibrin clot(not soluble)

        ThrombinXIII XIIIa

        (Digestion of Fibrin)

        Fibrinolysis

        Fibrinolysis Overview

        Destroys fibrin fibers

        Destroys the scab (dried wound)

        Maintains vessel integrity

        Fibrinolysis Overview

        Fibrin =cement fibers

        Plasmin

        Plasmin digests fibrin

        t-PA

        Pro Urokinase

        Urokinase

        PAI-1PAI-1

        Plasminogen Plasmin

        1st Step

        2nd Step

        Fibrinolysis Cascade

        t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin

        Extrinsic pathway(endothelia l cells)

        Intrinsic pathway(plasma)

        Fibrin clot

        D-dimerFibrin degradation products

        Fibrin

        TAFIa

        APAntiplasmin(amp a2-MG)

        PK Kallikrein

        XII

        Fibrinolysis Releases D-dimers

        D-dimer presence fibrin has been formed and digested in patients body

        Normal D-dimer level no thrombosis occurred in the patient

        Basic Pathophysiology of DIC

        Disseminated Intravascular Coagulation (DIC)

        Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management

        Clinical Manifestations of DICOrgan Ischemic Hemorrhagic

        Skin Pupura Fulminans Petechiae

        Gangrene Echymoses

        Acral cyanosis Oozing

        CNS Deliriumcoma Intracranial

        Infarcts Bleeding

        Renal OliguriaAzotemia Hematuria

        Cortical Necrosis

        Cardiovascular Myocardial dysfunction

        Pulmonary DyspneaHypoxia Hemorrhagic lung

        Infarct

        Gastrointestinal Ulcers infarcts Massive hemorrhage

        Endocrine Adrenal infarcts

        Purpura Fulminans with DIC Due to Meningococcal Sepsis

        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

        Clinical Conditions Associated With DIC

        Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

        Frequency of DIC in Selected Disease States

        Disease Frequency

        Gram-negative sepsis 30-50

        Severe trauma and systemic inflammation 50-70

        Metastasized tumors 15

        Abruptio placentaamniotic fluid embolism 50

        Severe preeclampsia 7

        Giant hemangioma 25

        Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

        Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017

        Underlying Diseases in DIC Patients

        In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively

        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

        Epidemiology of DIC

        Impact of DIC Status on Mortality - 1

        Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8

        Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC

        Impact of DIC Status on Mortality - 2

        Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

        Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients

        Impact of Age on Mortality in DIC Patients

        Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

        Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)

        Pathophysiology of DIC

        Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

        Pathogenesis of DIC in Sepsis

        Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15

        Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC

        Host Response in Severe Sepsis

        Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral

        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

        Organ Failure in Severe Sepsis

        Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure

        Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51

        Mechanism of DIC in Organ Failure

        Underlying condition(sepsis trauma)

        Cytokines

        TF-mediatedactivation of coagulation

        Depression of inhibitory systems

        Reducesfibrinolysis

        Fibrin deposition

        Organ failure

        Inadequate fibrin removal

        Fibrinformation

        Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )

        Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705

        Interaction of Inflammation and Coagulation in Sepsis

        Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines

        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

        Mechanism of Multiple Organ Failure in DIC

        Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

        Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

        lipopolysaccharides

        cytokines

        coagulation activation

        mononuclear cell

        tissue factor

        Diverse and Opposing Effects of Thrombin

        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

        Coagulation and Fibrinolysis in DIC

        Soluble fibrin Polymer

        XIIIa

        D-Dimer

        E

        Fibrin clot

        Fibrin Degradation Products

        Fibrinogen Thrombin

        Fibrinogen Degradation

        Products

        D E

        Plasmin

        DFM + fibrinopeptides

        Soluble FM ComplexesPre-throm

        boticPost-throm

        botic

        Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

        Mechanism of DIC

        THROMBOSIS

        Fibrin

        Blood activationEndothelial lysisTF expression

        BLEEDING

        FDPs

        D-Dimer

        Plasmin

        Pathophysiology of DIC

        1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

        thromboplastin influx of activated cells (monocytes macrophages)

        Results in an intravascular deposition of fibrin

        Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

        Second step Consumption and depletion of coagulation factors inhibitors (Protein C

        Protein S AT) and platelets Local fibrinolytic response

        bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

        FDP and D-Dimer

        Bleeding

        Pathophysiology of DIC - Mechanism

        Systemic activation of coagulation

        Intravasculardepositionof fibrin

        Thrombosis of small and midsize vessels

        and organ failure

        Depletion of platelets and

        coagulation factors

        Bleeding

        Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

        Pathophysiology of DIC ndash 2 Types of Clinical pictures

        Chronic = non - overt DICMay be unrecognized clinically

        Acute = overt DIClife threatening bleedingor multiple organ failure

        Sub-Acute and Non-Overt DIC Clinical Findings

        Compensated non-overt DIC Steady low level or intermittent activation

        bull Compensated by increased production of coagulation components and platelets

        Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

        Risk of decompensation leading to overt DIC

        Pathophysiology of Overt DIC

        Massive activation of coagulation and fibrinolysis

        Does not allow for compensatory efforts

        Rapid depletion of coagulation factors inhibitors and platelets

        Thrombosis multiple organ failures

        Bleeding complications and shock

        Physiopathology of DIC ndash Overt DIC Findings

        Thrombin generation

        Thrombosis

        Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

        Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

        Plasmin generationHemorrhage

        bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

        bull Tachycardia hypotension edema

        Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

        Pathogenesis Pathways in DIC

        Cytokines

        TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

        fibrin inadequateformation fibrin removal

        Fibrin deposition

        Inflammation

        Coagulation

        Stago Celebrates Lab Week 2017

        NA

        Stago 247 Educational Webinar Sites

        wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

        wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

        Stago Educational Apps

        HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

        iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

        BREAK

        Diagnostic and Management Approach for DIC

        Diagnosis of DIC

        Clinical diagnosis is obvious in cases of overt DIC

        Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

        Lab Diagnosis of DIC ndash Markers of Factor Consumption

        Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

        Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

        Important to recognize simultaneous formation of thrombin and plasmin

        Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

        Lab Diagnosis of DIC ndash Screening Tests

        Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

        Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

        fibrinogen level) repeat testing assesses progression

        Screening tests not clinically specific or sensitive for DIC

        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

        Laboratory Changes in Overt DIC

        DIC Diagnostic Practices Over Time

        Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

        British Journal of Haematology Overt DIC Score

        Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

        ISTH Step by Step DIC Algorithm

        Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

        US Based Validation of ISTH DIC Score

        When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

        Differential Diagnosis in DIC

        aHUS atypical hemolytic uremic syndrome

        HUS hemolytic uremic syndrome

        HIT heparin-induced thrombocytopenia

        ITP immune thrombocytopenic purpura

        TTP thrombotic thrombocytopenic purpura

        DIC and MAHA

        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

        lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

        When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

        DIC Management Goals

        Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

        Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

        DIC Management and Treatment

        Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

        Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

        requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

        Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

        DIC Management Strategies

        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

        Anticoagulant Factor Concentrate Treatment

        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

        Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

        Anticoagulant Factor Concentrate Treatment Trials

        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

        Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

        Markers of Thrombin amp Plasmin Generation in DIC

        D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

        Cut-off value

        Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

        degradation products Sensitive assay typically with cutoff adapted for DIC

        D-dimer FDPs and DIC

        D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

        Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

        Follow Up of DIC State of Disease

        Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

        Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

        FMD-Dimer in DIC Major Differences

        onset of thrombosis

        days

        Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

        FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

        D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

        of Abnormal Results in Patients with Confirmed and Suspected DIC

        0

        20

        40

        60

        80

        100

        94 85 90N = 62

        Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

        Positivity of Test Results ISTH Score and Disease State

        Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

        Red bar positive for 2 points of DIC score

        Pink bar positive for 1-2 points of DIC score

        HT hematopoietic tumor

        IF infection

        SC solid cancer

        Markers in Patients with or without DIC

        Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

        HT hematopoietic tumorIF infectionSC solid cancer

        Comparing an Automated FM vs Manual FSP Test

        Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

        Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

        Automated (Mitsubishi) vs Automated (Stago)

        In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

        Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

        Diagnostic Performance of FM and D-dimer in DIC

        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

        Diagnostic Performance of FM and D-dimer in DIC

        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

        In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

        Diagnostic Performance of FM and D-dimer in DIC

        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

        In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

        Diagnostic Performance of FM and D-dimer in DIC

        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

        In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

        Diagnostic Performance of FM and D-dimer in DIC

        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

        Diagnostic Performance of FM and D-dimer in DIC

        Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

        No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

        Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

        Diagnostic Performance of FM and D-dimer in DIC

        Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

        Non Overt DIC Overt DIC

        AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

        Trends in Markers of DIC for Different Patients

        Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

        Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

        Trends in Markers of DIC for Different Patients

        Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

        FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

        28 day outcome survival

        28 day outcome death

        Determination of Cutoffs of FM and D-dimer in DIC

        Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

        Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

        Determination of Cutoffs of FM and D-dimer in DIC

        Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

        Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

        DIC Case Studies

        Case Study 1 - Presentation

        18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

        Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

        WBC count 77 KμL 423 ndash 907 x KμL

        RBC count 17 MμL 137 ndash 175 x MμL

        Hemoglobin 67 gdL 137 ndash 175 gdL

        Hematocrit 195 401 ndash 510

        MCV 95 fL 790 ndash 922 fL

        MPV 12 fL 94 ndash 124 fL

        Platelet count 9 KμL 161 ndash 347 KμL

        Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

        Lymphocytes monocytes eosinophils basophils all below normal range

        PT 47 sec (corrected on mixing study) 116 ndash 152 sec

        APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

        Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

        D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

        Case Study 1 ndash Microscopy

        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

        Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

        Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

        DIC due to TF release by APL blasts

        Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

        Transfusions to replace factors along with platelets and RBCs during APL treatment

        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

        20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

        Case Study 2 ndash Presentation

        TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

        PT 30 sec 113 ndash 146 sec

        APTT 75 sec 25 ndash 34 sec

        D-dimer 078 microgml FEU lt050 microgml FEU

        Fibrinogen 92 mgdl 150-400 mgdl

        pH 728 738 to 742

        PaO2 570 mmHg 80-100 mmHg

        WBC 33 times 103mm3 40-11 times 103mm3

        ALT 111 IUL 0ndash34 IUL

        AST 61 IUL 0ndash34 IUL

        BUN 303 mgdL 08-13 mgdL

        Case Study 2 ndash Lab Results

        Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

        Case Study 2 ndash Diagnosis

        60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

        Case Study 3 ndash Presentation

        TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

        PT 228 sec 113 ndash 146 sec

        APTT 45 sec 25 ndash 34 sec

        D-dimer 080 microgml FEU lt050 microgmL FEU

        Fibrinogen 82 mgdL 150-400 mgdL

        FV Normal 70-120

        FVII Normal 55-170

        FVIII Normal 60-150

        Protein C Normal 70-130

        Hb 134 gdL 14-16 gdL

        WBC 81 times 103mm3 40-11 times 103mm3

        ALT 32 IUL 0ndash34 IUL

        AST 28 IUL 0ndash34 IUL

        BUN 09 mgdL 08-13 mgdL

        Case Study 3 ndash Lab Results

        Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

        Case Study 3 ndash Diagnosis and Therapy

        Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

        Case Study 4 ndash Presentation

        TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

        PT 28 sec 113 ndash 146 sec

        APTT 71 sec 25 ndash 34 sec

        D-dimer 31 microgmL FEU lt050 microgml FEU

        Fibrinogen 92 mgdL 150-400 mgdl

        FV Normal 70-120

        FVII Normal 55-170

        FVIII Normal 60-150

        Protein C Normal 70-130

        Hb 158 gdL 14-16 gdL

        WBC 71 times 103mm3 40-11 times 103mm3

        ALT 60 IUL 0ndash34 IUL

        AST 47 IUL 0ndash34 IUL

        BUN 38 mgdL 08-13 mgdL

        Case Study 4 ndash Lab Results

        Lyme disease with DICProvide antibiotics with supportive measures

        Case Study 4 ndash Diagnosis

        55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

        Case Study 5 ndash Presentation

        Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

        Case Study 5 ndash Lab Results and Time Course

        Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

        TEST RESULT REFERENCE RANGE

        Platelet count 33 x 109L 150-450 x 109L

        PT 215 sec 103 ndash 128 sec

        APTT 44 sec 26 ndash 36 sec

        D-dimer 20 microgmL FEU lt025 microgml FEU

        Fibrinogen 34 mgdL 200-375 mgdl

        FII FV FVIII Low Not reported (NR)

        FVII FIX FX vWF Normal NR

        Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

        DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

        dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

        (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

        (D) Illustration demonstrating repair

        Case Study 5 ndash Diagnosis and Treatment

        Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

        29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

        Case Study 6 ndash Presentation

        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

        Case Study 6 ndash Lab Results

        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

        TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

        PT 63 sec gt control 113 ndash 146 sec

        INR 658 1 ndash 125

        APTT 80 sec gt control 25 ndash 34 sec

        D-dimer gt200 microgmL DDU 02 microgmL DDU

        Urine exam Proteinuria and hematuria 150-400 mgdl

        Albumin 28 gdL NR

        Hb 58 gdL NR

        LDH 1196 UL NR

        SGPT 144 IU NR

        SGOT 88 IU NR

        Bilirubin 32 mgdL NR

        DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

        day postop

        Case Study 6 ndash Diagnosis and Treatment

        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

        HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

        Case Study 6 ndash Discussion

        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

        44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

        Case Study 7 ndash Presentation

        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

        On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

        Case Study 7 ndash Presentation

        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

        Case Study 7 ndash Lab Results vs Time

        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

        Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

        Case Study 7 ndash Diagnosis and Treatment

        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

        On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

        Case Study 7 ndash Diagnosis and Treatment

        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

        DIC Take Home Messages

        Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

        Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

        DIC

        Thank you Questions

        • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
        • Learning Objectives
        • Slide Number 3
        • Slide Number 4
        • Slide Number 5
        • Slide Number 6
        • Slide Number 7
        • Slide Number 8
        • Wound Sealing
        • The Three Steps of Hemostasis
        • Vessel Wall
        • Slide Number 12
        • Slide Number 13
        • Platelet Structure UnactivatedActivated
        • Primary Hemostasis
        • Primary Hemostasis Assays
        • Slide Number 17
        • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
        • Slide Number 19
        • Coagulation factors
        • Coagulation Assay Mechanisms
        • Slide Number 22
        • Fibrin Formation
        • Slide Number 24
        • Fibrinolysis Overview
        • Fibrinolysis Overview
        • Slide Number 27
        • Fibrinolysis Releases D-dimers
        • Basic Pathophysiology of DIC
        • Disseminated Intravascular Coagulation (DIC)
        • Purpura Fulminans with DIC Due to Meningococcal Sepsis
        • Clinical Conditions Associated With DIC
        • Frequency of DIC in Selected Disease States
        • Underlying Diseases in DIC Patients
        • Slide Number 36
        • Slide Number 37
        • Slide Number 38
        • Slide Number 39
        • Pathophysiology of DIC
        • Pathogenesis of DIC in Sepsis
        • Host Response in Severe Sepsis
        • Organ Failure in Severe Sepsis
        • Mechanism of DIC in Organ Failure
        • Interaction of Inflammation and Coagulation in Sepsis
        • Slide Number 47
        • Diverse and Opposing Effects of Thrombin
        • Coagulation and Fibrinolysis in DIC
        • Mechanism of DIC
        • Pathophysiology of DIC
        • Pathophysiology of DIC - Mechanism
        • Pathophysiology of DIC ndash 2 Types of Clinical pictures
        • Sub-Acute and Non-Overt DIC Clinical Findings
        • Pathophysiology of Overt DIC
        • Physiopathology of DIC ndash Overt DIC Findings
        • Slide Number 57
        • Slide Number 58
        • Slide Number 59
        • Slide Number 60
        • Slide Number 61
        • BREAK
        • Diagnostic and Management Approach for DIC
        • Diagnosis of DIC
        • Lab Diagnosis of DIC ndash Markers of Factor Consumption
        • Lab Diagnosis of DIC ndash Screening Tests
        • Slide Number 67
        • Slide Number 68
        • British Journal of Haematology Overt DIC Score
        • Slide Number 70
        • Slide Number 71
        • Slide Number 72
        • Slide Number 73
        • DIC Management Goals
        • DIC Management and Treatment
        • DIC Management Strategies
        • Anticoagulant Factor Concentrate Treatment
        • Anticoagulant Factor Concentrate Treatment Trials
        • Markers of Thrombin amp Plasmin Generation in DIC
        • D-dimer FDPs and DIC
        • D-Dimer and FDPs in DIC
        • Follow Up of DIC State of Disease
        • FMD-Dimer in DIC Major Differences
        • of Abnormal Results in Patients with Confirmed and Suspected DIC
        • Slide Number 85
        • Slide Number 86
        • Comparing an Automated FM vs Manual FSP Test
        • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
        • Diagnostic Performance of FM and D-dimer in DIC
        • Diagnostic Performance of FM and D-dimer in DIC
        • Diagnostic Performance of FM and D-dimer in DIC
        • Diagnostic Performance of FM and D-dimer in DIC
        • Diagnostic Performance of FM and D-dimer in DIC
        • Slide Number 94
        • Slide Number 95
        • Slide Number 96
        • Slide Number 97
        • Slide Number 98
        • Slide Number 99
        • DIC Case Studies
        • Case Study 1 - Presentation
        • Case Study 1 ndash Lab Results
        • Case Study 1 ndash Microscopy
        • Case Study 1 ndash Diagnosis and Therapy
        • Slide Number 105
        • Slide Number 106
        • Slide Number 107
        • Slide Number 108
        • Slide Number 109
        • Slide Number 110
        • Slide Number 111
        • Slide Number 112
        • Slide Number 113
        • Slide Number 114
        • Slide Number 115
        • Slide Number 116
        • Slide Number 117
        • Slide Number 118
        • Slide Number 119
        • Slide Number 120
        • Slide Number 121
        • Slide Number 122
        • Slide Number 123
        • Slide Number 124
        • Slide Number 125
        • DIC Take Home Messages
        • Slide Number 127
        • Slide Number 128

          Blood Circulation

          ARTERIES

          VEINS

          Occurs through blood vessels

          The heart pumps the blood

          Arteries carry oxygenated blood away from the heart under high pressure

          Veins carry de-oxygenated blood back to the heart under low pressure

          Hemostasis

          The mechanism that maintains blood fluidity

          Keeps a balance between bleeding and clotting

          2 major roles Stop bleeding by repairing holes in blood vessels Clean up the inside of blood vessels Removes temporary clot that stopped bleeding Sweeps off needless deposits that may cause blood flow

          blockages

          Bleeding =

          Hemorrhage

          Blood clot =

          Thrombosis

          Two Major Diseases Linked to Hemostatic Abnormalities

          Physiology of Hemostasis

          Wound Sealing

          EFFRACbreak in vessel

          FIBRINOLYSIS

          clot destruction

          PRIMARYHEMOSTASIS

          PLASMATICCOAGULATION

          strong clot

          wound sealing blood flow plusmn stopped

          The Three Steps of Hemostasis

          Primary Hemostasis Interaction between vessel wall platelets and adhesive proteins platelet clot

          Coagulation Consolidation of the platelet thrombus insoluble fibrin net

          bull Coagulation factors and inhibitors

          Fibrinolysis Clot lysis clot is digested

          bull Fibrinolytic activators and inhibitors

          Vessel Wall

          Intact endothelium non thrombogenic Synthesis of vasodilators (prostacyclin) No reaction either with platelets or factors

          Sub endotheliumTissue Endothelium

          blood

          When a vessel wall is damaged Exposure of the subendothelium Platelet adhesion Initiation of the mechanisms of coagulation and fibrinolysis

          PlateletsFactors

          Sub endotheliumTissue Endothelium

          blood

          Vessel Wall Damage

          Aim is to clog the damaged vessel ( asymp bricks without cement )

          Primary Hemostasis

          Platelet Structure UnactivatedActivated

          GpIb-IX-V

          GpIIb-IIIa

          α granules (raw materials)PF4 β-TG Fibrinogen VWF Factor V and PAI-1

          dense granules (energy and glue)ATP ADP SerotoninCa2+ Mg2+ P

          Hillman Robert S Ault Kenneth A Rinder Henry M Hematology in Clinical Practice 4th Edition McGraw-Hill New York NY 2005

          Primary Hemostasis

          2) activation2nd shape changeamp release

          platelet at rest 1) adhesion1st shape change

          3) aggregation(not reversible)

          Vasoconstriction occurs first

          Platelets then aggregate on the break in the vessel wall

          Primary Hemostasis AssaysRoutine Platelet count PT APTT TT

          Follow-up von Willebrand Factor Antigen determination Activity Factor VIII PFA-100 Platelet aggregation studies

          SpecializedSend Out Activation markers (b-TG PF4 GPV) Specialized tests for platelet function

          Aim is to strengthen the platelet plug

          Coagulation

          Coagulation is a balancebetween pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis

          THROMBIN

          Fibrinogen Fibrin

          bull Triggering agentsbull pro-enzyme enzyme (serine-protease FIIa FVIIa FIXa FXa)bull Cofactors (FVa amp FVIIIa)

          bull Serine-protease inhibitor Antithrombin (AT) bull Cofactorsinhibitors Protein C Sbull Tissue factor pathway inhibitor (TFPI)

          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

          Coagulation Cascade Schematic

          Coagulation factors

          Historic name

          Fibrinogen

          Prothrombin

          Proaccelerin

          Proconvertin

          Anti-hemophilic factor A

          Anti-hemophilic factor B

          Stuart factor

          Rosenthal factor

          Hageman factor

          Fibrin Stabilizing Factor

          Factor

          I

          II

          V

          VII

          VIII

          IX

          X

          XI

          XII

          XIII

          Function

          Substrate

          Pro-enzyme

          Pro-cofactor

          Pro-enzyme

          Pro-cofactor

          Pro-enzyme

          Pro-enzyme

          Pro-enzyme

          Pro-enzyme

          Pro-enzyme

          Pro-enzyme = Zymogen activation Active Enzyme

          Coagulation Assay Mechanisms

          aPTT Based

          PT Based

          PT Based

          Fibrin Under Microscope

          Weisel JW Structure of fibrin impact on clot stability J Thromb Haemost 2007 5 Suppl 1 116-24

          Low thrombin concentration

          High thrombin concentration

          Fibrin Formation

          Soluble FibrinPolymer

          ThrombinFibrinogen

          FM+ fibrinopeptides A amp B

          Stabilized Fibrin clot(not soluble)

          ThrombinXIII XIIIa

          (Digestion of Fibrin)

          Fibrinolysis

          Fibrinolysis Overview

          Destroys fibrin fibers

          Destroys the scab (dried wound)

          Maintains vessel integrity

          Fibrinolysis Overview

          Fibrin =cement fibers

          Plasmin

          Plasmin digests fibrin

          t-PA

          Pro Urokinase

          Urokinase

          PAI-1PAI-1

          Plasminogen Plasmin

          1st Step

          2nd Step

          Fibrinolysis Cascade

          t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin

          Extrinsic pathway(endothelia l cells)

          Intrinsic pathway(plasma)

          Fibrin clot

          D-dimerFibrin degradation products

          Fibrin

          TAFIa

          APAntiplasmin(amp a2-MG)

          PK Kallikrein

          XII

          Fibrinolysis Releases D-dimers

          D-dimer presence fibrin has been formed and digested in patients body

          Normal D-dimer level no thrombosis occurred in the patient

          Basic Pathophysiology of DIC

          Disseminated Intravascular Coagulation (DIC)

          Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management

          Clinical Manifestations of DICOrgan Ischemic Hemorrhagic

          Skin Pupura Fulminans Petechiae

          Gangrene Echymoses

          Acral cyanosis Oozing

          CNS Deliriumcoma Intracranial

          Infarcts Bleeding

          Renal OliguriaAzotemia Hematuria

          Cortical Necrosis

          Cardiovascular Myocardial dysfunction

          Pulmonary DyspneaHypoxia Hemorrhagic lung

          Infarct

          Gastrointestinal Ulcers infarcts Massive hemorrhage

          Endocrine Adrenal infarcts

          Purpura Fulminans with DIC Due to Meningococcal Sepsis

          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

          Clinical Conditions Associated With DIC

          Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

          Frequency of DIC in Selected Disease States

          Disease Frequency

          Gram-negative sepsis 30-50

          Severe trauma and systemic inflammation 50-70

          Metastasized tumors 15

          Abruptio placentaamniotic fluid embolism 50

          Severe preeclampsia 7

          Giant hemangioma 25

          Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

          Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017

          Underlying Diseases in DIC Patients

          In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively

          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

          Epidemiology of DIC

          Impact of DIC Status on Mortality - 1

          Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8

          Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC

          Impact of DIC Status on Mortality - 2

          Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

          Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients

          Impact of Age on Mortality in DIC Patients

          Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

          Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)

          Pathophysiology of DIC

          Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

          Pathogenesis of DIC in Sepsis

          Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15

          Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC

          Host Response in Severe Sepsis

          Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral

          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

          Organ Failure in Severe Sepsis

          Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure

          Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51

          Mechanism of DIC in Organ Failure

          Underlying condition(sepsis trauma)

          Cytokines

          TF-mediatedactivation of coagulation

          Depression of inhibitory systems

          Reducesfibrinolysis

          Fibrin deposition

          Organ failure

          Inadequate fibrin removal

          Fibrinformation

          Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )

          Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705

          Interaction of Inflammation and Coagulation in Sepsis

          Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines

          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

          Mechanism of Multiple Organ Failure in DIC

          Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

          Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

          lipopolysaccharides

          cytokines

          coagulation activation

          mononuclear cell

          tissue factor

          Diverse and Opposing Effects of Thrombin

          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

          Coagulation and Fibrinolysis in DIC

          Soluble fibrin Polymer

          XIIIa

          D-Dimer

          E

          Fibrin clot

          Fibrin Degradation Products

          Fibrinogen Thrombin

          Fibrinogen Degradation

          Products

          D E

          Plasmin

          DFM + fibrinopeptides

          Soluble FM ComplexesPre-throm

          boticPost-throm

          botic

          Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

          Mechanism of DIC

          THROMBOSIS

          Fibrin

          Blood activationEndothelial lysisTF expression

          BLEEDING

          FDPs

          D-Dimer

          Plasmin

          Pathophysiology of DIC

          1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

          thromboplastin influx of activated cells (monocytes macrophages)

          Results in an intravascular deposition of fibrin

          Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

          Second step Consumption and depletion of coagulation factors inhibitors (Protein C

          Protein S AT) and platelets Local fibrinolytic response

          bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

          FDP and D-Dimer

          Bleeding

          Pathophysiology of DIC - Mechanism

          Systemic activation of coagulation

          Intravasculardepositionof fibrin

          Thrombosis of small and midsize vessels

          and organ failure

          Depletion of platelets and

          coagulation factors

          Bleeding

          Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

          Pathophysiology of DIC ndash 2 Types of Clinical pictures

          Chronic = non - overt DICMay be unrecognized clinically

          Acute = overt DIClife threatening bleedingor multiple organ failure

          Sub-Acute and Non-Overt DIC Clinical Findings

          Compensated non-overt DIC Steady low level or intermittent activation

          bull Compensated by increased production of coagulation components and platelets

          Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

          Risk of decompensation leading to overt DIC

          Pathophysiology of Overt DIC

          Massive activation of coagulation and fibrinolysis

          Does not allow for compensatory efforts

          Rapid depletion of coagulation factors inhibitors and platelets

          Thrombosis multiple organ failures

          Bleeding complications and shock

          Physiopathology of DIC ndash Overt DIC Findings

          Thrombin generation

          Thrombosis

          Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

          Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

          Plasmin generationHemorrhage

          bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

          bull Tachycardia hypotension edema

          Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

          Pathogenesis Pathways in DIC

          Cytokines

          TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

          fibrin inadequateformation fibrin removal

          Fibrin deposition

          Inflammation

          Coagulation

          Stago Celebrates Lab Week 2017

          NA

          Stago 247 Educational Webinar Sites

          wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

          wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

          Stago Educational Apps

          HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

          iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

          BREAK

          Diagnostic and Management Approach for DIC

          Diagnosis of DIC

          Clinical diagnosis is obvious in cases of overt DIC

          Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

          Lab Diagnosis of DIC ndash Markers of Factor Consumption

          Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

          Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

          Important to recognize simultaneous formation of thrombin and plasmin

          Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

          Lab Diagnosis of DIC ndash Screening Tests

          Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

          Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

          fibrinogen level) repeat testing assesses progression

          Screening tests not clinically specific or sensitive for DIC

          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

          Laboratory Changes in Overt DIC

          DIC Diagnostic Practices Over Time

          Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

          British Journal of Haematology Overt DIC Score

          Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

          ISTH Step by Step DIC Algorithm

          Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

          US Based Validation of ISTH DIC Score

          When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

          Differential Diagnosis in DIC

          aHUS atypical hemolytic uremic syndrome

          HUS hemolytic uremic syndrome

          HIT heparin-induced thrombocytopenia

          ITP immune thrombocytopenic purpura

          TTP thrombotic thrombocytopenic purpura

          DIC and MAHA

          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

          lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

          When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

          DIC Management Goals

          Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

          Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

          DIC Management and Treatment

          Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

          Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

          requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

          Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

          DIC Management Strategies

          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

          Anticoagulant Factor Concentrate Treatment

          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

          Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

          Anticoagulant Factor Concentrate Treatment Trials

          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

          Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

          Markers of Thrombin amp Plasmin Generation in DIC

          D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

          Cut-off value

          Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

          degradation products Sensitive assay typically with cutoff adapted for DIC

          D-dimer FDPs and DIC

          D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

          Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

          Follow Up of DIC State of Disease

          Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

          Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

          FMD-Dimer in DIC Major Differences

          onset of thrombosis

          days

          Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

          FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

          D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

          of Abnormal Results in Patients with Confirmed and Suspected DIC

          0

          20

          40

          60

          80

          100

          94 85 90N = 62

          Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

          Positivity of Test Results ISTH Score and Disease State

          Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

          Red bar positive for 2 points of DIC score

          Pink bar positive for 1-2 points of DIC score

          HT hematopoietic tumor

          IF infection

          SC solid cancer

          Markers in Patients with or without DIC

          Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

          HT hematopoietic tumorIF infectionSC solid cancer

          Comparing an Automated FM vs Manual FSP Test

          Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

          Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

          Automated (Mitsubishi) vs Automated (Stago)

          In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

          Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

          Diagnostic Performance of FM and D-dimer in DIC

          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

          Diagnostic Performance of FM and D-dimer in DIC

          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

          In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

          Diagnostic Performance of FM and D-dimer in DIC

          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

          In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

          Diagnostic Performance of FM and D-dimer in DIC

          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

          In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

          Diagnostic Performance of FM and D-dimer in DIC

          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

          Diagnostic Performance of FM and D-dimer in DIC

          Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

          No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

          Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

          Diagnostic Performance of FM and D-dimer in DIC

          Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

          Non Overt DIC Overt DIC

          AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

          Trends in Markers of DIC for Different Patients

          Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

          Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

          Trends in Markers of DIC for Different Patients

          Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

          FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

          28 day outcome survival

          28 day outcome death

          Determination of Cutoffs of FM and D-dimer in DIC

          Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

          Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

          Determination of Cutoffs of FM and D-dimer in DIC

          Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

          Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

          DIC Case Studies

          Case Study 1 - Presentation

          18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

          Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

          WBC count 77 KμL 423 ndash 907 x KμL

          RBC count 17 MμL 137 ndash 175 x MμL

          Hemoglobin 67 gdL 137 ndash 175 gdL

          Hematocrit 195 401 ndash 510

          MCV 95 fL 790 ndash 922 fL

          MPV 12 fL 94 ndash 124 fL

          Platelet count 9 KμL 161 ndash 347 KμL

          Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

          Lymphocytes monocytes eosinophils basophils all below normal range

          PT 47 sec (corrected on mixing study) 116 ndash 152 sec

          APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

          Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

          D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

          Case Study 1 ndash Microscopy

          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

          Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

          Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

          DIC due to TF release by APL blasts

          Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

          Transfusions to replace factors along with platelets and RBCs during APL treatment

          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

          20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

          Case Study 2 ndash Presentation

          TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

          PT 30 sec 113 ndash 146 sec

          APTT 75 sec 25 ndash 34 sec

          D-dimer 078 microgml FEU lt050 microgml FEU

          Fibrinogen 92 mgdl 150-400 mgdl

          pH 728 738 to 742

          PaO2 570 mmHg 80-100 mmHg

          WBC 33 times 103mm3 40-11 times 103mm3

          ALT 111 IUL 0ndash34 IUL

          AST 61 IUL 0ndash34 IUL

          BUN 303 mgdL 08-13 mgdL

          Case Study 2 ndash Lab Results

          Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

          Case Study 2 ndash Diagnosis

          60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

          Case Study 3 ndash Presentation

          TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

          PT 228 sec 113 ndash 146 sec

          APTT 45 sec 25 ndash 34 sec

          D-dimer 080 microgml FEU lt050 microgmL FEU

          Fibrinogen 82 mgdL 150-400 mgdL

          FV Normal 70-120

          FVII Normal 55-170

          FVIII Normal 60-150

          Protein C Normal 70-130

          Hb 134 gdL 14-16 gdL

          WBC 81 times 103mm3 40-11 times 103mm3

          ALT 32 IUL 0ndash34 IUL

          AST 28 IUL 0ndash34 IUL

          BUN 09 mgdL 08-13 mgdL

          Case Study 3 ndash Lab Results

          Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

          Case Study 3 ndash Diagnosis and Therapy

          Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

          Case Study 4 ndash Presentation

          TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

          PT 28 sec 113 ndash 146 sec

          APTT 71 sec 25 ndash 34 sec

          D-dimer 31 microgmL FEU lt050 microgml FEU

          Fibrinogen 92 mgdL 150-400 mgdl

          FV Normal 70-120

          FVII Normal 55-170

          FVIII Normal 60-150

          Protein C Normal 70-130

          Hb 158 gdL 14-16 gdL

          WBC 71 times 103mm3 40-11 times 103mm3

          ALT 60 IUL 0ndash34 IUL

          AST 47 IUL 0ndash34 IUL

          BUN 38 mgdL 08-13 mgdL

          Case Study 4 ndash Lab Results

          Lyme disease with DICProvide antibiotics with supportive measures

          Case Study 4 ndash Diagnosis

          55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

          Case Study 5 ndash Presentation

          Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

          Case Study 5 ndash Lab Results and Time Course

          Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

          TEST RESULT REFERENCE RANGE

          Platelet count 33 x 109L 150-450 x 109L

          PT 215 sec 103 ndash 128 sec

          APTT 44 sec 26 ndash 36 sec

          D-dimer 20 microgmL FEU lt025 microgml FEU

          Fibrinogen 34 mgdL 200-375 mgdl

          FII FV FVIII Low Not reported (NR)

          FVII FIX FX vWF Normal NR

          Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

          DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

          dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

          (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

          (D) Illustration demonstrating repair

          Case Study 5 ndash Diagnosis and Treatment

          Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

          29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

          Case Study 6 ndash Presentation

          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

          Case Study 6 ndash Lab Results

          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

          TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

          PT 63 sec gt control 113 ndash 146 sec

          INR 658 1 ndash 125

          APTT 80 sec gt control 25 ndash 34 sec

          D-dimer gt200 microgmL DDU 02 microgmL DDU

          Urine exam Proteinuria and hematuria 150-400 mgdl

          Albumin 28 gdL NR

          Hb 58 gdL NR

          LDH 1196 UL NR

          SGPT 144 IU NR

          SGOT 88 IU NR

          Bilirubin 32 mgdL NR

          DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

          day postop

          Case Study 6 ndash Diagnosis and Treatment

          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

          HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

          Case Study 6 ndash Discussion

          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

          44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

          Case Study 7 ndash Presentation

          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

          On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

          Case Study 7 ndash Presentation

          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

          Case Study 7 ndash Lab Results vs Time

          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

          Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

          Case Study 7 ndash Diagnosis and Treatment

          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

          On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

          Case Study 7 ndash Diagnosis and Treatment

          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

          DIC Take Home Messages

          Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

          Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

          DIC

          Thank you Questions

          • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
          • Learning Objectives
          • Slide Number 3
          • Slide Number 4
          • Slide Number 5
          • Slide Number 6
          • Slide Number 7
          • Slide Number 8
          • Wound Sealing
          • The Three Steps of Hemostasis
          • Vessel Wall
          • Slide Number 12
          • Slide Number 13
          • Platelet Structure UnactivatedActivated
          • Primary Hemostasis
          • Primary Hemostasis Assays
          • Slide Number 17
          • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
          • Slide Number 19
          • Coagulation factors
          • Coagulation Assay Mechanisms
          • Slide Number 22
          • Fibrin Formation
          • Slide Number 24
          • Fibrinolysis Overview
          • Fibrinolysis Overview
          • Slide Number 27
          • Fibrinolysis Releases D-dimers
          • Basic Pathophysiology of DIC
          • Disseminated Intravascular Coagulation (DIC)
          • Purpura Fulminans with DIC Due to Meningococcal Sepsis
          • Clinical Conditions Associated With DIC
          • Frequency of DIC in Selected Disease States
          • Underlying Diseases in DIC Patients
          • Slide Number 36
          • Slide Number 37
          • Slide Number 38
          • Slide Number 39
          • Pathophysiology of DIC
          • Pathogenesis of DIC in Sepsis
          • Host Response in Severe Sepsis
          • Organ Failure in Severe Sepsis
          • Mechanism of DIC in Organ Failure
          • Interaction of Inflammation and Coagulation in Sepsis
          • Slide Number 47
          • Diverse and Opposing Effects of Thrombin
          • Coagulation and Fibrinolysis in DIC
          • Mechanism of DIC
          • Pathophysiology of DIC
          • Pathophysiology of DIC - Mechanism
          • Pathophysiology of DIC ndash 2 Types of Clinical pictures
          • Sub-Acute and Non-Overt DIC Clinical Findings
          • Pathophysiology of Overt DIC
          • Physiopathology of DIC ndash Overt DIC Findings
          • Slide Number 57
          • Slide Number 58
          • Slide Number 59
          • Slide Number 60
          • Slide Number 61
          • BREAK
          • Diagnostic and Management Approach for DIC
          • Diagnosis of DIC
          • Lab Diagnosis of DIC ndash Markers of Factor Consumption
          • Lab Diagnosis of DIC ndash Screening Tests
          • Slide Number 67
          • Slide Number 68
          • British Journal of Haematology Overt DIC Score
          • Slide Number 70
          • Slide Number 71
          • Slide Number 72
          • Slide Number 73
          • DIC Management Goals
          • DIC Management and Treatment
          • DIC Management Strategies
          • Anticoagulant Factor Concentrate Treatment
          • Anticoagulant Factor Concentrate Treatment Trials
          • Markers of Thrombin amp Plasmin Generation in DIC
          • D-dimer FDPs and DIC
          • D-Dimer and FDPs in DIC
          • Follow Up of DIC State of Disease
          • FMD-Dimer in DIC Major Differences
          • of Abnormal Results in Patients with Confirmed and Suspected DIC
          • Slide Number 85
          • Slide Number 86
          • Comparing an Automated FM vs Manual FSP Test
          • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
          • Diagnostic Performance of FM and D-dimer in DIC
          • Diagnostic Performance of FM and D-dimer in DIC
          • Diagnostic Performance of FM and D-dimer in DIC
          • Diagnostic Performance of FM and D-dimer in DIC
          • Diagnostic Performance of FM and D-dimer in DIC
          • Slide Number 94
          • Slide Number 95
          • Slide Number 96
          • Slide Number 97
          • Slide Number 98
          • Slide Number 99
          • DIC Case Studies
          • Case Study 1 - Presentation
          • Case Study 1 ndash Lab Results
          • Case Study 1 ndash Microscopy
          • Case Study 1 ndash Diagnosis and Therapy
          • Slide Number 105
          • Slide Number 106
          • Slide Number 107
          • Slide Number 108
          • Slide Number 109
          • Slide Number 110
          • Slide Number 111
          • Slide Number 112
          • Slide Number 113
          • Slide Number 114
          • Slide Number 115
          • Slide Number 116
          • Slide Number 117
          • Slide Number 118
          • Slide Number 119
          • Slide Number 120
          • Slide Number 121
          • Slide Number 122
          • Slide Number 123
          • Slide Number 124
          • Slide Number 125
          • DIC Take Home Messages
          • Slide Number 127
          • Slide Number 128

            Hemostasis

            The mechanism that maintains blood fluidity

            Keeps a balance between bleeding and clotting

            2 major roles Stop bleeding by repairing holes in blood vessels Clean up the inside of blood vessels Removes temporary clot that stopped bleeding Sweeps off needless deposits that may cause blood flow

            blockages

            Bleeding =

            Hemorrhage

            Blood clot =

            Thrombosis

            Two Major Diseases Linked to Hemostatic Abnormalities

            Physiology of Hemostasis

            Wound Sealing

            EFFRACbreak in vessel

            FIBRINOLYSIS

            clot destruction

            PRIMARYHEMOSTASIS

            PLASMATICCOAGULATION

            strong clot

            wound sealing blood flow plusmn stopped

            The Three Steps of Hemostasis

            Primary Hemostasis Interaction between vessel wall platelets and adhesive proteins platelet clot

            Coagulation Consolidation of the platelet thrombus insoluble fibrin net

            bull Coagulation factors and inhibitors

            Fibrinolysis Clot lysis clot is digested

            bull Fibrinolytic activators and inhibitors

            Vessel Wall

            Intact endothelium non thrombogenic Synthesis of vasodilators (prostacyclin) No reaction either with platelets or factors

            Sub endotheliumTissue Endothelium

            blood

            When a vessel wall is damaged Exposure of the subendothelium Platelet adhesion Initiation of the mechanisms of coagulation and fibrinolysis

            PlateletsFactors

            Sub endotheliumTissue Endothelium

            blood

            Vessel Wall Damage

            Aim is to clog the damaged vessel ( asymp bricks without cement )

            Primary Hemostasis

            Platelet Structure UnactivatedActivated

            GpIb-IX-V

            GpIIb-IIIa

            α granules (raw materials)PF4 β-TG Fibrinogen VWF Factor V and PAI-1

            dense granules (energy and glue)ATP ADP SerotoninCa2+ Mg2+ P

            Hillman Robert S Ault Kenneth A Rinder Henry M Hematology in Clinical Practice 4th Edition McGraw-Hill New York NY 2005

            Primary Hemostasis

            2) activation2nd shape changeamp release

            platelet at rest 1) adhesion1st shape change

            3) aggregation(not reversible)

            Vasoconstriction occurs first

            Platelets then aggregate on the break in the vessel wall

            Primary Hemostasis AssaysRoutine Platelet count PT APTT TT

            Follow-up von Willebrand Factor Antigen determination Activity Factor VIII PFA-100 Platelet aggregation studies

            SpecializedSend Out Activation markers (b-TG PF4 GPV) Specialized tests for platelet function

            Aim is to strengthen the platelet plug

            Coagulation

            Coagulation is a balancebetween pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis

            THROMBIN

            Fibrinogen Fibrin

            bull Triggering agentsbull pro-enzyme enzyme (serine-protease FIIa FVIIa FIXa FXa)bull Cofactors (FVa amp FVIIIa)

            bull Serine-protease inhibitor Antithrombin (AT) bull Cofactorsinhibitors Protein C Sbull Tissue factor pathway inhibitor (TFPI)

            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

            Coagulation Cascade Schematic

            Coagulation factors

            Historic name

            Fibrinogen

            Prothrombin

            Proaccelerin

            Proconvertin

            Anti-hemophilic factor A

            Anti-hemophilic factor B

            Stuart factor

            Rosenthal factor

            Hageman factor

            Fibrin Stabilizing Factor

            Factor

            I

            II

            V

            VII

            VIII

            IX

            X

            XI

            XII

            XIII

            Function

            Substrate

            Pro-enzyme

            Pro-cofactor

            Pro-enzyme

            Pro-cofactor

            Pro-enzyme

            Pro-enzyme

            Pro-enzyme

            Pro-enzyme

            Pro-enzyme

            Pro-enzyme = Zymogen activation Active Enzyme

            Coagulation Assay Mechanisms

            aPTT Based

            PT Based

            PT Based

            Fibrin Under Microscope

            Weisel JW Structure of fibrin impact on clot stability J Thromb Haemost 2007 5 Suppl 1 116-24

            Low thrombin concentration

            High thrombin concentration

            Fibrin Formation

            Soluble FibrinPolymer

            ThrombinFibrinogen

            FM+ fibrinopeptides A amp B

            Stabilized Fibrin clot(not soluble)

            ThrombinXIII XIIIa

            (Digestion of Fibrin)

            Fibrinolysis

            Fibrinolysis Overview

            Destroys fibrin fibers

            Destroys the scab (dried wound)

            Maintains vessel integrity

            Fibrinolysis Overview

            Fibrin =cement fibers

            Plasmin

            Plasmin digests fibrin

            t-PA

            Pro Urokinase

            Urokinase

            PAI-1PAI-1

            Plasminogen Plasmin

            1st Step

            2nd Step

            Fibrinolysis Cascade

            t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin

            Extrinsic pathway(endothelia l cells)

            Intrinsic pathway(plasma)

            Fibrin clot

            D-dimerFibrin degradation products

            Fibrin

            TAFIa

            APAntiplasmin(amp a2-MG)

            PK Kallikrein

            XII

            Fibrinolysis Releases D-dimers

            D-dimer presence fibrin has been formed and digested in patients body

            Normal D-dimer level no thrombosis occurred in the patient

            Basic Pathophysiology of DIC

            Disseminated Intravascular Coagulation (DIC)

            Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management

            Clinical Manifestations of DICOrgan Ischemic Hemorrhagic

            Skin Pupura Fulminans Petechiae

            Gangrene Echymoses

            Acral cyanosis Oozing

            CNS Deliriumcoma Intracranial

            Infarcts Bleeding

            Renal OliguriaAzotemia Hematuria

            Cortical Necrosis

            Cardiovascular Myocardial dysfunction

            Pulmonary DyspneaHypoxia Hemorrhagic lung

            Infarct

            Gastrointestinal Ulcers infarcts Massive hemorrhage

            Endocrine Adrenal infarcts

            Purpura Fulminans with DIC Due to Meningococcal Sepsis

            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

            Clinical Conditions Associated With DIC

            Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

            Frequency of DIC in Selected Disease States

            Disease Frequency

            Gram-negative sepsis 30-50

            Severe trauma and systemic inflammation 50-70

            Metastasized tumors 15

            Abruptio placentaamniotic fluid embolism 50

            Severe preeclampsia 7

            Giant hemangioma 25

            Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

            Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017

            Underlying Diseases in DIC Patients

            In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively

            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

            Epidemiology of DIC

            Impact of DIC Status on Mortality - 1

            Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8

            Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC

            Impact of DIC Status on Mortality - 2

            Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

            Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients

            Impact of Age on Mortality in DIC Patients

            Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

            Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)

            Pathophysiology of DIC

            Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

            Pathogenesis of DIC in Sepsis

            Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15

            Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC

            Host Response in Severe Sepsis

            Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral

            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

            Organ Failure in Severe Sepsis

            Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure

            Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51

            Mechanism of DIC in Organ Failure

            Underlying condition(sepsis trauma)

            Cytokines

            TF-mediatedactivation of coagulation

            Depression of inhibitory systems

            Reducesfibrinolysis

            Fibrin deposition

            Organ failure

            Inadequate fibrin removal

            Fibrinformation

            Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )

            Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705

            Interaction of Inflammation and Coagulation in Sepsis

            Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines

            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

            Mechanism of Multiple Organ Failure in DIC

            Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

            Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

            lipopolysaccharides

            cytokines

            coagulation activation

            mononuclear cell

            tissue factor

            Diverse and Opposing Effects of Thrombin

            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

            Coagulation and Fibrinolysis in DIC

            Soluble fibrin Polymer

            XIIIa

            D-Dimer

            E

            Fibrin clot

            Fibrin Degradation Products

            Fibrinogen Thrombin

            Fibrinogen Degradation

            Products

            D E

            Plasmin

            DFM + fibrinopeptides

            Soluble FM ComplexesPre-throm

            boticPost-throm

            botic

            Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

            Mechanism of DIC

            THROMBOSIS

            Fibrin

            Blood activationEndothelial lysisTF expression

            BLEEDING

            FDPs

            D-Dimer

            Plasmin

            Pathophysiology of DIC

            1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

            thromboplastin influx of activated cells (monocytes macrophages)

            Results in an intravascular deposition of fibrin

            Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

            Second step Consumption and depletion of coagulation factors inhibitors (Protein C

            Protein S AT) and platelets Local fibrinolytic response

            bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

            FDP and D-Dimer

            Bleeding

            Pathophysiology of DIC - Mechanism

            Systemic activation of coagulation

            Intravasculardepositionof fibrin

            Thrombosis of small and midsize vessels

            and organ failure

            Depletion of platelets and

            coagulation factors

            Bleeding

            Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

            Pathophysiology of DIC ndash 2 Types of Clinical pictures

            Chronic = non - overt DICMay be unrecognized clinically

            Acute = overt DIClife threatening bleedingor multiple organ failure

            Sub-Acute and Non-Overt DIC Clinical Findings

            Compensated non-overt DIC Steady low level or intermittent activation

            bull Compensated by increased production of coagulation components and platelets

            Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

            Risk of decompensation leading to overt DIC

            Pathophysiology of Overt DIC

            Massive activation of coagulation and fibrinolysis

            Does not allow for compensatory efforts

            Rapid depletion of coagulation factors inhibitors and platelets

            Thrombosis multiple organ failures

            Bleeding complications and shock

            Physiopathology of DIC ndash Overt DIC Findings

            Thrombin generation

            Thrombosis

            Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

            Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

            Plasmin generationHemorrhage

            bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

            bull Tachycardia hypotension edema

            Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

            Pathogenesis Pathways in DIC

            Cytokines

            TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

            fibrin inadequateformation fibrin removal

            Fibrin deposition

            Inflammation

            Coagulation

            Stago Celebrates Lab Week 2017

            NA

            Stago 247 Educational Webinar Sites

            wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

            wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

            Stago Educational Apps

            HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

            iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

            BREAK

            Diagnostic and Management Approach for DIC

            Diagnosis of DIC

            Clinical diagnosis is obvious in cases of overt DIC

            Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

            Lab Diagnosis of DIC ndash Markers of Factor Consumption

            Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

            Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

            Important to recognize simultaneous formation of thrombin and plasmin

            Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

            Lab Diagnosis of DIC ndash Screening Tests

            Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

            Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

            fibrinogen level) repeat testing assesses progression

            Screening tests not clinically specific or sensitive for DIC

            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

            Laboratory Changes in Overt DIC

            DIC Diagnostic Practices Over Time

            Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

            British Journal of Haematology Overt DIC Score

            Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

            ISTH Step by Step DIC Algorithm

            Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

            US Based Validation of ISTH DIC Score

            When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

            Differential Diagnosis in DIC

            aHUS atypical hemolytic uremic syndrome

            HUS hemolytic uremic syndrome

            HIT heparin-induced thrombocytopenia

            ITP immune thrombocytopenic purpura

            TTP thrombotic thrombocytopenic purpura

            DIC and MAHA

            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

            lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

            When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

            DIC Management Goals

            Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

            Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

            DIC Management and Treatment

            Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

            Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

            requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

            Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

            DIC Management Strategies

            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

            Anticoagulant Factor Concentrate Treatment

            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

            Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

            Anticoagulant Factor Concentrate Treatment Trials

            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

            Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

            Markers of Thrombin amp Plasmin Generation in DIC

            D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

            Cut-off value

            Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

            degradation products Sensitive assay typically with cutoff adapted for DIC

            D-dimer FDPs and DIC

            D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

            Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

            Follow Up of DIC State of Disease

            Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

            Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

            FMD-Dimer in DIC Major Differences

            onset of thrombosis

            days

            Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

            FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

            D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

            of Abnormal Results in Patients with Confirmed and Suspected DIC

            0

            20

            40

            60

            80

            100

            94 85 90N = 62

            Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

            Positivity of Test Results ISTH Score and Disease State

            Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

            Red bar positive for 2 points of DIC score

            Pink bar positive for 1-2 points of DIC score

            HT hematopoietic tumor

            IF infection

            SC solid cancer

            Markers in Patients with or without DIC

            Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

            HT hematopoietic tumorIF infectionSC solid cancer

            Comparing an Automated FM vs Manual FSP Test

            Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

            Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

            Automated (Mitsubishi) vs Automated (Stago)

            In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

            Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

            Diagnostic Performance of FM and D-dimer in DIC

            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

            Diagnostic Performance of FM and D-dimer in DIC

            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

            In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

            Diagnostic Performance of FM and D-dimer in DIC

            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

            In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

            Diagnostic Performance of FM and D-dimer in DIC

            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

            In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

            Diagnostic Performance of FM and D-dimer in DIC

            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

            Diagnostic Performance of FM and D-dimer in DIC

            Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

            No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

            Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

            Diagnostic Performance of FM and D-dimer in DIC

            Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

            Non Overt DIC Overt DIC

            AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

            Trends in Markers of DIC for Different Patients

            Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

            Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

            Trends in Markers of DIC for Different Patients

            Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

            FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

            28 day outcome survival

            28 day outcome death

            Determination of Cutoffs of FM and D-dimer in DIC

            Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

            Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

            Determination of Cutoffs of FM and D-dimer in DIC

            Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

            Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

            DIC Case Studies

            Case Study 1 - Presentation

            18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

            Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

            WBC count 77 KμL 423 ndash 907 x KμL

            RBC count 17 MμL 137 ndash 175 x MμL

            Hemoglobin 67 gdL 137 ndash 175 gdL

            Hematocrit 195 401 ndash 510

            MCV 95 fL 790 ndash 922 fL

            MPV 12 fL 94 ndash 124 fL

            Platelet count 9 KμL 161 ndash 347 KμL

            Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

            Lymphocytes monocytes eosinophils basophils all below normal range

            PT 47 sec (corrected on mixing study) 116 ndash 152 sec

            APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

            Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

            D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

            Case Study 1 ndash Microscopy

            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

            Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

            Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

            DIC due to TF release by APL blasts

            Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

            Transfusions to replace factors along with platelets and RBCs during APL treatment

            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

            20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

            Case Study 2 ndash Presentation

            TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

            PT 30 sec 113 ndash 146 sec

            APTT 75 sec 25 ndash 34 sec

            D-dimer 078 microgml FEU lt050 microgml FEU

            Fibrinogen 92 mgdl 150-400 mgdl

            pH 728 738 to 742

            PaO2 570 mmHg 80-100 mmHg

            WBC 33 times 103mm3 40-11 times 103mm3

            ALT 111 IUL 0ndash34 IUL

            AST 61 IUL 0ndash34 IUL

            BUN 303 mgdL 08-13 mgdL

            Case Study 2 ndash Lab Results

            Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

            Case Study 2 ndash Diagnosis

            60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

            Case Study 3 ndash Presentation

            TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

            PT 228 sec 113 ndash 146 sec

            APTT 45 sec 25 ndash 34 sec

            D-dimer 080 microgml FEU lt050 microgmL FEU

            Fibrinogen 82 mgdL 150-400 mgdL

            FV Normal 70-120

            FVII Normal 55-170

            FVIII Normal 60-150

            Protein C Normal 70-130

            Hb 134 gdL 14-16 gdL

            WBC 81 times 103mm3 40-11 times 103mm3

            ALT 32 IUL 0ndash34 IUL

            AST 28 IUL 0ndash34 IUL

            BUN 09 mgdL 08-13 mgdL

            Case Study 3 ndash Lab Results

            Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

            Case Study 3 ndash Diagnosis and Therapy

            Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

            Case Study 4 ndash Presentation

            TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

            PT 28 sec 113 ndash 146 sec

            APTT 71 sec 25 ndash 34 sec

            D-dimer 31 microgmL FEU lt050 microgml FEU

            Fibrinogen 92 mgdL 150-400 mgdl

            FV Normal 70-120

            FVII Normal 55-170

            FVIII Normal 60-150

            Protein C Normal 70-130

            Hb 158 gdL 14-16 gdL

            WBC 71 times 103mm3 40-11 times 103mm3

            ALT 60 IUL 0ndash34 IUL

            AST 47 IUL 0ndash34 IUL

            BUN 38 mgdL 08-13 mgdL

            Case Study 4 ndash Lab Results

            Lyme disease with DICProvide antibiotics with supportive measures

            Case Study 4 ndash Diagnosis

            55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

            Case Study 5 ndash Presentation

            Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

            Case Study 5 ndash Lab Results and Time Course

            Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

            TEST RESULT REFERENCE RANGE

            Platelet count 33 x 109L 150-450 x 109L

            PT 215 sec 103 ndash 128 sec

            APTT 44 sec 26 ndash 36 sec

            D-dimer 20 microgmL FEU lt025 microgml FEU

            Fibrinogen 34 mgdL 200-375 mgdl

            FII FV FVIII Low Not reported (NR)

            FVII FIX FX vWF Normal NR

            Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

            DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

            dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

            (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

            (D) Illustration demonstrating repair

            Case Study 5 ndash Diagnosis and Treatment

            Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

            29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

            Case Study 6 ndash Presentation

            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

            Case Study 6 ndash Lab Results

            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

            TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

            PT 63 sec gt control 113 ndash 146 sec

            INR 658 1 ndash 125

            APTT 80 sec gt control 25 ndash 34 sec

            D-dimer gt200 microgmL DDU 02 microgmL DDU

            Urine exam Proteinuria and hematuria 150-400 mgdl

            Albumin 28 gdL NR

            Hb 58 gdL NR

            LDH 1196 UL NR

            SGPT 144 IU NR

            SGOT 88 IU NR

            Bilirubin 32 mgdL NR

            DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

            day postop

            Case Study 6 ndash Diagnosis and Treatment

            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

            HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

            Case Study 6 ndash Discussion

            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

            44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

            Case Study 7 ndash Presentation

            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

            On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

            Case Study 7 ndash Presentation

            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

            Case Study 7 ndash Lab Results vs Time

            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

            Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

            Case Study 7 ndash Diagnosis and Treatment

            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

            On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

            Case Study 7 ndash Diagnosis and Treatment

            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

            DIC Take Home Messages

            Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

            Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

            DIC

            Thank you Questions

            • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
            • Learning Objectives
            • Slide Number 3
            • Slide Number 4
            • Slide Number 5
            • Slide Number 6
            • Slide Number 7
            • Slide Number 8
            • Wound Sealing
            • The Three Steps of Hemostasis
            • Vessel Wall
            • Slide Number 12
            • Slide Number 13
            • Platelet Structure UnactivatedActivated
            • Primary Hemostasis
            • Primary Hemostasis Assays
            • Slide Number 17
            • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
            • Slide Number 19
            • Coagulation factors
            • Coagulation Assay Mechanisms
            • Slide Number 22
            • Fibrin Formation
            • Slide Number 24
            • Fibrinolysis Overview
            • Fibrinolysis Overview
            • Slide Number 27
            • Fibrinolysis Releases D-dimers
            • Basic Pathophysiology of DIC
            • Disseminated Intravascular Coagulation (DIC)
            • Purpura Fulminans with DIC Due to Meningococcal Sepsis
            • Clinical Conditions Associated With DIC
            • Frequency of DIC in Selected Disease States
            • Underlying Diseases in DIC Patients
            • Slide Number 36
            • Slide Number 37
            • Slide Number 38
            • Slide Number 39
            • Pathophysiology of DIC
            • Pathogenesis of DIC in Sepsis
            • Host Response in Severe Sepsis
            • Organ Failure in Severe Sepsis
            • Mechanism of DIC in Organ Failure
            • Interaction of Inflammation and Coagulation in Sepsis
            • Slide Number 47
            • Diverse and Opposing Effects of Thrombin
            • Coagulation and Fibrinolysis in DIC
            • Mechanism of DIC
            • Pathophysiology of DIC
            • Pathophysiology of DIC - Mechanism
            • Pathophysiology of DIC ndash 2 Types of Clinical pictures
            • Sub-Acute and Non-Overt DIC Clinical Findings
            • Pathophysiology of Overt DIC
            • Physiopathology of DIC ndash Overt DIC Findings
            • Slide Number 57
            • Slide Number 58
            • Slide Number 59
            • Slide Number 60
            • Slide Number 61
            • BREAK
            • Diagnostic and Management Approach for DIC
            • Diagnosis of DIC
            • Lab Diagnosis of DIC ndash Markers of Factor Consumption
            • Lab Diagnosis of DIC ndash Screening Tests
            • Slide Number 67
            • Slide Number 68
            • British Journal of Haematology Overt DIC Score
            • Slide Number 70
            • Slide Number 71
            • Slide Number 72
            • Slide Number 73
            • DIC Management Goals
            • DIC Management and Treatment
            • DIC Management Strategies
            • Anticoagulant Factor Concentrate Treatment
            • Anticoagulant Factor Concentrate Treatment Trials
            • Markers of Thrombin amp Plasmin Generation in DIC
            • D-dimer FDPs and DIC
            • D-Dimer and FDPs in DIC
            • Follow Up of DIC State of Disease
            • FMD-Dimer in DIC Major Differences
            • of Abnormal Results in Patients with Confirmed and Suspected DIC
            • Slide Number 85
            • Slide Number 86
            • Comparing an Automated FM vs Manual FSP Test
            • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
            • Diagnostic Performance of FM and D-dimer in DIC
            • Diagnostic Performance of FM and D-dimer in DIC
            • Diagnostic Performance of FM and D-dimer in DIC
            • Diagnostic Performance of FM and D-dimer in DIC
            • Diagnostic Performance of FM and D-dimer in DIC
            • Slide Number 94
            • Slide Number 95
            • Slide Number 96
            • Slide Number 97
            • Slide Number 98
            • Slide Number 99
            • DIC Case Studies
            • Case Study 1 - Presentation
            • Case Study 1 ndash Lab Results
            • Case Study 1 ndash Microscopy
            • Case Study 1 ndash Diagnosis and Therapy
            • Slide Number 105
            • Slide Number 106
            • Slide Number 107
            • Slide Number 108
            • Slide Number 109
            • Slide Number 110
            • Slide Number 111
            • Slide Number 112
            • Slide Number 113
            • Slide Number 114
            • Slide Number 115
            • Slide Number 116
            • Slide Number 117
            • Slide Number 118
            • Slide Number 119
            • Slide Number 120
            • Slide Number 121
            • Slide Number 122
            • Slide Number 123
            • Slide Number 124
            • Slide Number 125
            • DIC Take Home Messages
            • Slide Number 127
            • Slide Number 128

              Bleeding =

              Hemorrhage

              Blood clot =

              Thrombosis

              Two Major Diseases Linked to Hemostatic Abnormalities

              Physiology of Hemostasis

              Wound Sealing

              EFFRACbreak in vessel

              FIBRINOLYSIS

              clot destruction

              PRIMARYHEMOSTASIS

              PLASMATICCOAGULATION

              strong clot

              wound sealing blood flow plusmn stopped

              The Three Steps of Hemostasis

              Primary Hemostasis Interaction between vessel wall platelets and adhesive proteins platelet clot

              Coagulation Consolidation of the platelet thrombus insoluble fibrin net

              bull Coagulation factors and inhibitors

              Fibrinolysis Clot lysis clot is digested

              bull Fibrinolytic activators and inhibitors

              Vessel Wall

              Intact endothelium non thrombogenic Synthesis of vasodilators (prostacyclin) No reaction either with platelets or factors

              Sub endotheliumTissue Endothelium

              blood

              When a vessel wall is damaged Exposure of the subendothelium Platelet adhesion Initiation of the mechanisms of coagulation and fibrinolysis

              PlateletsFactors

              Sub endotheliumTissue Endothelium

              blood

              Vessel Wall Damage

              Aim is to clog the damaged vessel ( asymp bricks without cement )

              Primary Hemostasis

              Platelet Structure UnactivatedActivated

              GpIb-IX-V

              GpIIb-IIIa

              α granules (raw materials)PF4 β-TG Fibrinogen VWF Factor V and PAI-1

              dense granules (energy and glue)ATP ADP SerotoninCa2+ Mg2+ P

              Hillman Robert S Ault Kenneth A Rinder Henry M Hematology in Clinical Practice 4th Edition McGraw-Hill New York NY 2005

              Primary Hemostasis

              2) activation2nd shape changeamp release

              platelet at rest 1) adhesion1st shape change

              3) aggregation(not reversible)

              Vasoconstriction occurs first

              Platelets then aggregate on the break in the vessel wall

              Primary Hemostasis AssaysRoutine Platelet count PT APTT TT

              Follow-up von Willebrand Factor Antigen determination Activity Factor VIII PFA-100 Platelet aggregation studies

              SpecializedSend Out Activation markers (b-TG PF4 GPV) Specialized tests for platelet function

              Aim is to strengthen the platelet plug

              Coagulation

              Coagulation is a balancebetween pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis

              THROMBIN

              Fibrinogen Fibrin

              bull Triggering agentsbull pro-enzyme enzyme (serine-protease FIIa FVIIa FIXa FXa)bull Cofactors (FVa amp FVIIIa)

              bull Serine-protease inhibitor Antithrombin (AT) bull Cofactorsinhibitors Protein C Sbull Tissue factor pathway inhibitor (TFPI)

              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

              Coagulation Cascade Schematic

              Coagulation factors

              Historic name

              Fibrinogen

              Prothrombin

              Proaccelerin

              Proconvertin

              Anti-hemophilic factor A

              Anti-hemophilic factor B

              Stuart factor

              Rosenthal factor

              Hageman factor

              Fibrin Stabilizing Factor

              Factor

              I

              II

              V

              VII

              VIII

              IX

              X

              XI

              XII

              XIII

              Function

              Substrate

              Pro-enzyme

              Pro-cofactor

              Pro-enzyme

              Pro-cofactor

              Pro-enzyme

              Pro-enzyme

              Pro-enzyme

              Pro-enzyme

              Pro-enzyme

              Pro-enzyme = Zymogen activation Active Enzyme

              Coagulation Assay Mechanisms

              aPTT Based

              PT Based

              PT Based

              Fibrin Under Microscope

              Weisel JW Structure of fibrin impact on clot stability J Thromb Haemost 2007 5 Suppl 1 116-24

              Low thrombin concentration

              High thrombin concentration

              Fibrin Formation

              Soluble FibrinPolymer

              ThrombinFibrinogen

              FM+ fibrinopeptides A amp B

              Stabilized Fibrin clot(not soluble)

              ThrombinXIII XIIIa

              (Digestion of Fibrin)

              Fibrinolysis

              Fibrinolysis Overview

              Destroys fibrin fibers

              Destroys the scab (dried wound)

              Maintains vessel integrity

              Fibrinolysis Overview

              Fibrin =cement fibers

              Plasmin

              Plasmin digests fibrin

              t-PA

              Pro Urokinase

              Urokinase

              PAI-1PAI-1

              Plasminogen Plasmin

              1st Step

              2nd Step

              Fibrinolysis Cascade

              t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin

              Extrinsic pathway(endothelia l cells)

              Intrinsic pathway(plasma)

              Fibrin clot

              D-dimerFibrin degradation products

              Fibrin

              TAFIa

              APAntiplasmin(amp a2-MG)

              PK Kallikrein

              XII

              Fibrinolysis Releases D-dimers

              D-dimer presence fibrin has been formed and digested in patients body

              Normal D-dimer level no thrombosis occurred in the patient

              Basic Pathophysiology of DIC

              Disseminated Intravascular Coagulation (DIC)

              Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management

              Clinical Manifestations of DICOrgan Ischemic Hemorrhagic

              Skin Pupura Fulminans Petechiae

              Gangrene Echymoses

              Acral cyanosis Oozing

              CNS Deliriumcoma Intracranial

              Infarcts Bleeding

              Renal OliguriaAzotemia Hematuria

              Cortical Necrosis

              Cardiovascular Myocardial dysfunction

              Pulmonary DyspneaHypoxia Hemorrhagic lung

              Infarct

              Gastrointestinal Ulcers infarcts Massive hemorrhage

              Endocrine Adrenal infarcts

              Purpura Fulminans with DIC Due to Meningococcal Sepsis

              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

              Clinical Conditions Associated With DIC

              Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

              Frequency of DIC in Selected Disease States

              Disease Frequency

              Gram-negative sepsis 30-50

              Severe trauma and systemic inflammation 50-70

              Metastasized tumors 15

              Abruptio placentaamniotic fluid embolism 50

              Severe preeclampsia 7

              Giant hemangioma 25

              Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

              Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017

              Underlying Diseases in DIC Patients

              In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively

              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

              Epidemiology of DIC

              Impact of DIC Status on Mortality - 1

              Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8

              Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC

              Impact of DIC Status on Mortality - 2

              Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

              Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients

              Impact of Age on Mortality in DIC Patients

              Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

              Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)

              Pathophysiology of DIC

              Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

              Pathogenesis of DIC in Sepsis

              Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15

              Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC

              Host Response in Severe Sepsis

              Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral

              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

              Organ Failure in Severe Sepsis

              Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure

              Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51

              Mechanism of DIC in Organ Failure

              Underlying condition(sepsis trauma)

              Cytokines

              TF-mediatedactivation of coagulation

              Depression of inhibitory systems

              Reducesfibrinolysis

              Fibrin deposition

              Organ failure

              Inadequate fibrin removal

              Fibrinformation

              Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )

              Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705

              Interaction of Inflammation and Coagulation in Sepsis

              Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines

              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

              Mechanism of Multiple Organ Failure in DIC

              Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

              Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

              lipopolysaccharides

              cytokines

              coagulation activation

              mononuclear cell

              tissue factor

              Diverse and Opposing Effects of Thrombin

              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

              Coagulation and Fibrinolysis in DIC

              Soluble fibrin Polymer

              XIIIa

              D-Dimer

              E

              Fibrin clot

              Fibrin Degradation Products

              Fibrinogen Thrombin

              Fibrinogen Degradation

              Products

              D E

              Plasmin

              DFM + fibrinopeptides

              Soluble FM ComplexesPre-throm

              boticPost-throm

              botic

              Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

              Mechanism of DIC

              THROMBOSIS

              Fibrin

              Blood activationEndothelial lysisTF expression

              BLEEDING

              FDPs

              D-Dimer

              Plasmin

              Pathophysiology of DIC

              1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

              thromboplastin influx of activated cells (monocytes macrophages)

              Results in an intravascular deposition of fibrin

              Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

              Second step Consumption and depletion of coagulation factors inhibitors (Protein C

              Protein S AT) and platelets Local fibrinolytic response

              bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

              FDP and D-Dimer

              Bleeding

              Pathophysiology of DIC - Mechanism

              Systemic activation of coagulation

              Intravasculardepositionof fibrin

              Thrombosis of small and midsize vessels

              and organ failure

              Depletion of platelets and

              coagulation factors

              Bleeding

              Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

              Pathophysiology of DIC ndash 2 Types of Clinical pictures

              Chronic = non - overt DICMay be unrecognized clinically

              Acute = overt DIClife threatening bleedingor multiple organ failure

              Sub-Acute and Non-Overt DIC Clinical Findings

              Compensated non-overt DIC Steady low level or intermittent activation

              bull Compensated by increased production of coagulation components and platelets

              Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

              Risk of decompensation leading to overt DIC

              Pathophysiology of Overt DIC

              Massive activation of coagulation and fibrinolysis

              Does not allow for compensatory efforts

              Rapid depletion of coagulation factors inhibitors and platelets

              Thrombosis multiple organ failures

              Bleeding complications and shock

              Physiopathology of DIC ndash Overt DIC Findings

              Thrombin generation

              Thrombosis

              Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

              Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

              Plasmin generationHemorrhage

              bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

              bull Tachycardia hypotension edema

              Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

              Pathogenesis Pathways in DIC

              Cytokines

              TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

              fibrin inadequateformation fibrin removal

              Fibrin deposition

              Inflammation

              Coagulation

              Stago Celebrates Lab Week 2017

              NA

              Stago 247 Educational Webinar Sites

              wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

              wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

              Stago Educational Apps

              HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

              iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

              BREAK

              Diagnostic and Management Approach for DIC

              Diagnosis of DIC

              Clinical diagnosis is obvious in cases of overt DIC

              Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

              Lab Diagnosis of DIC ndash Markers of Factor Consumption

              Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

              Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

              Important to recognize simultaneous formation of thrombin and plasmin

              Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

              Lab Diagnosis of DIC ndash Screening Tests

              Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

              Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

              fibrinogen level) repeat testing assesses progression

              Screening tests not clinically specific or sensitive for DIC

              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

              Laboratory Changes in Overt DIC

              DIC Diagnostic Practices Over Time

              Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

              British Journal of Haematology Overt DIC Score

              Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

              ISTH Step by Step DIC Algorithm

              Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

              US Based Validation of ISTH DIC Score

              When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

              Differential Diagnosis in DIC

              aHUS atypical hemolytic uremic syndrome

              HUS hemolytic uremic syndrome

              HIT heparin-induced thrombocytopenia

              ITP immune thrombocytopenic purpura

              TTP thrombotic thrombocytopenic purpura

              DIC and MAHA

              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

              lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

              When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

              DIC Management Goals

              Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

              Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

              DIC Management and Treatment

              Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

              Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

              requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

              Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

              DIC Management Strategies

              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

              Anticoagulant Factor Concentrate Treatment

              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

              Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

              Anticoagulant Factor Concentrate Treatment Trials

              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

              Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

              Markers of Thrombin amp Plasmin Generation in DIC

              D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

              Cut-off value

              Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

              degradation products Sensitive assay typically with cutoff adapted for DIC

              D-dimer FDPs and DIC

              D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

              Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

              Follow Up of DIC State of Disease

              Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

              Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

              FMD-Dimer in DIC Major Differences

              onset of thrombosis

              days

              Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

              FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

              D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

              of Abnormal Results in Patients with Confirmed and Suspected DIC

              0

              20

              40

              60

              80

              100

              94 85 90N = 62

              Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

              Positivity of Test Results ISTH Score and Disease State

              Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

              Red bar positive for 2 points of DIC score

              Pink bar positive for 1-2 points of DIC score

              HT hematopoietic tumor

              IF infection

              SC solid cancer

              Markers in Patients with or without DIC

              Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

              HT hematopoietic tumorIF infectionSC solid cancer

              Comparing an Automated FM vs Manual FSP Test

              Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

              Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

              Automated (Mitsubishi) vs Automated (Stago)

              In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

              Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

              Diagnostic Performance of FM and D-dimer in DIC

              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

              Diagnostic Performance of FM and D-dimer in DIC

              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

              In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

              Diagnostic Performance of FM and D-dimer in DIC

              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

              In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

              Diagnostic Performance of FM and D-dimer in DIC

              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

              In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

              Diagnostic Performance of FM and D-dimer in DIC

              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

              Diagnostic Performance of FM and D-dimer in DIC

              Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

              No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

              Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

              Diagnostic Performance of FM and D-dimer in DIC

              Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

              Non Overt DIC Overt DIC

              AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

              Trends in Markers of DIC for Different Patients

              Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

              Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

              Trends in Markers of DIC for Different Patients

              Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

              FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

              28 day outcome survival

              28 day outcome death

              Determination of Cutoffs of FM and D-dimer in DIC

              Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

              Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

              Determination of Cutoffs of FM and D-dimer in DIC

              Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

              Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

              DIC Case Studies

              Case Study 1 - Presentation

              18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

              Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

              WBC count 77 KμL 423 ndash 907 x KμL

              RBC count 17 MμL 137 ndash 175 x MμL

              Hemoglobin 67 gdL 137 ndash 175 gdL

              Hematocrit 195 401 ndash 510

              MCV 95 fL 790 ndash 922 fL

              MPV 12 fL 94 ndash 124 fL

              Platelet count 9 KμL 161 ndash 347 KμL

              Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

              Lymphocytes monocytes eosinophils basophils all below normal range

              PT 47 sec (corrected on mixing study) 116 ndash 152 sec

              APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

              Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

              D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

              Case Study 1 ndash Microscopy

              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

              Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

              Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

              DIC due to TF release by APL blasts

              Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

              Transfusions to replace factors along with platelets and RBCs during APL treatment

              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

              20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

              Case Study 2 ndash Presentation

              TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

              PT 30 sec 113 ndash 146 sec

              APTT 75 sec 25 ndash 34 sec

              D-dimer 078 microgml FEU lt050 microgml FEU

              Fibrinogen 92 mgdl 150-400 mgdl

              pH 728 738 to 742

              PaO2 570 mmHg 80-100 mmHg

              WBC 33 times 103mm3 40-11 times 103mm3

              ALT 111 IUL 0ndash34 IUL

              AST 61 IUL 0ndash34 IUL

              BUN 303 mgdL 08-13 mgdL

              Case Study 2 ndash Lab Results

              Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

              Case Study 2 ndash Diagnosis

              60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

              Case Study 3 ndash Presentation

              TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

              PT 228 sec 113 ndash 146 sec

              APTT 45 sec 25 ndash 34 sec

              D-dimer 080 microgml FEU lt050 microgmL FEU

              Fibrinogen 82 mgdL 150-400 mgdL

              FV Normal 70-120

              FVII Normal 55-170

              FVIII Normal 60-150

              Protein C Normal 70-130

              Hb 134 gdL 14-16 gdL

              WBC 81 times 103mm3 40-11 times 103mm3

              ALT 32 IUL 0ndash34 IUL

              AST 28 IUL 0ndash34 IUL

              BUN 09 mgdL 08-13 mgdL

              Case Study 3 ndash Lab Results

              Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

              Case Study 3 ndash Diagnosis and Therapy

              Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

              Case Study 4 ndash Presentation

              TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

              PT 28 sec 113 ndash 146 sec

              APTT 71 sec 25 ndash 34 sec

              D-dimer 31 microgmL FEU lt050 microgml FEU

              Fibrinogen 92 mgdL 150-400 mgdl

              FV Normal 70-120

              FVII Normal 55-170

              FVIII Normal 60-150

              Protein C Normal 70-130

              Hb 158 gdL 14-16 gdL

              WBC 71 times 103mm3 40-11 times 103mm3

              ALT 60 IUL 0ndash34 IUL

              AST 47 IUL 0ndash34 IUL

              BUN 38 mgdL 08-13 mgdL

              Case Study 4 ndash Lab Results

              Lyme disease with DICProvide antibiotics with supportive measures

              Case Study 4 ndash Diagnosis

              55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

              Case Study 5 ndash Presentation

              Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

              Case Study 5 ndash Lab Results and Time Course

              Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

              TEST RESULT REFERENCE RANGE

              Platelet count 33 x 109L 150-450 x 109L

              PT 215 sec 103 ndash 128 sec

              APTT 44 sec 26 ndash 36 sec

              D-dimer 20 microgmL FEU lt025 microgml FEU

              Fibrinogen 34 mgdL 200-375 mgdl

              FII FV FVIII Low Not reported (NR)

              FVII FIX FX vWF Normal NR

              Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

              DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

              dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

              (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

              (D) Illustration demonstrating repair

              Case Study 5 ndash Diagnosis and Treatment

              Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

              29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

              Case Study 6 ndash Presentation

              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

              Case Study 6 ndash Lab Results

              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

              TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

              PT 63 sec gt control 113 ndash 146 sec

              INR 658 1 ndash 125

              APTT 80 sec gt control 25 ndash 34 sec

              D-dimer gt200 microgmL DDU 02 microgmL DDU

              Urine exam Proteinuria and hematuria 150-400 mgdl

              Albumin 28 gdL NR

              Hb 58 gdL NR

              LDH 1196 UL NR

              SGPT 144 IU NR

              SGOT 88 IU NR

              Bilirubin 32 mgdL NR

              DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

              day postop

              Case Study 6 ndash Diagnosis and Treatment

              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

              HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

              Case Study 6 ndash Discussion

              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

              44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

              Case Study 7 ndash Presentation

              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

              On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

              Case Study 7 ndash Presentation

              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

              Case Study 7 ndash Lab Results vs Time

              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

              Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

              Case Study 7 ndash Diagnosis and Treatment

              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

              On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

              Case Study 7 ndash Diagnosis and Treatment

              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

              DIC Take Home Messages

              Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

              Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

              DIC

              Thank you Questions

              • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
              • Learning Objectives
              • Slide Number 3
              • Slide Number 4
              • Slide Number 5
              • Slide Number 6
              • Slide Number 7
              • Slide Number 8
              • Wound Sealing
              • The Three Steps of Hemostasis
              • Vessel Wall
              • Slide Number 12
              • Slide Number 13
              • Platelet Structure UnactivatedActivated
              • Primary Hemostasis
              • Primary Hemostasis Assays
              • Slide Number 17
              • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
              • Slide Number 19
              • Coagulation factors
              • Coagulation Assay Mechanisms
              • Slide Number 22
              • Fibrin Formation
              • Slide Number 24
              • Fibrinolysis Overview
              • Fibrinolysis Overview
              • Slide Number 27
              • Fibrinolysis Releases D-dimers
              • Basic Pathophysiology of DIC
              • Disseminated Intravascular Coagulation (DIC)
              • Purpura Fulminans with DIC Due to Meningococcal Sepsis
              • Clinical Conditions Associated With DIC
              • Frequency of DIC in Selected Disease States
              • Underlying Diseases in DIC Patients
              • Slide Number 36
              • Slide Number 37
              • Slide Number 38
              • Slide Number 39
              • Pathophysiology of DIC
              • Pathogenesis of DIC in Sepsis
              • Host Response in Severe Sepsis
              • Organ Failure in Severe Sepsis
              • Mechanism of DIC in Organ Failure
              • Interaction of Inflammation and Coagulation in Sepsis
              • Slide Number 47
              • Diverse and Opposing Effects of Thrombin
              • Coagulation and Fibrinolysis in DIC
              • Mechanism of DIC
              • Pathophysiology of DIC
              • Pathophysiology of DIC - Mechanism
              • Pathophysiology of DIC ndash 2 Types of Clinical pictures
              • Sub-Acute and Non-Overt DIC Clinical Findings
              • Pathophysiology of Overt DIC
              • Physiopathology of DIC ndash Overt DIC Findings
              • Slide Number 57
              • Slide Number 58
              • Slide Number 59
              • Slide Number 60
              • Slide Number 61
              • BREAK
              • Diagnostic and Management Approach for DIC
              • Diagnosis of DIC
              • Lab Diagnosis of DIC ndash Markers of Factor Consumption
              • Lab Diagnosis of DIC ndash Screening Tests
              • Slide Number 67
              • Slide Number 68
              • British Journal of Haematology Overt DIC Score
              • Slide Number 70
              • Slide Number 71
              • Slide Number 72
              • Slide Number 73
              • DIC Management Goals
              • DIC Management and Treatment
              • DIC Management Strategies
              • Anticoagulant Factor Concentrate Treatment
              • Anticoagulant Factor Concentrate Treatment Trials
              • Markers of Thrombin amp Plasmin Generation in DIC
              • D-dimer FDPs and DIC
              • D-Dimer and FDPs in DIC
              • Follow Up of DIC State of Disease
              • FMD-Dimer in DIC Major Differences
              • of Abnormal Results in Patients with Confirmed and Suspected DIC
              • Slide Number 85
              • Slide Number 86
              • Comparing an Automated FM vs Manual FSP Test
              • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
              • Diagnostic Performance of FM and D-dimer in DIC
              • Diagnostic Performance of FM and D-dimer in DIC
              • Diagnostic Performance of FM and D-dimer in DIC
              • Diagnostic Performance of FM and D-dimer in DIC
              • Diagnostic Performance of FM and D-dimer in DIC
              • Slide Number 94
              • Slide Number 95
              • Slide Number 96
              • Slide Number 97
              • Slide Number 98
              • Slide Number 99
              • DIC Case Studies
              • Case Study 1 - Presentation
              • Case Study 1 ndash Lab Results
              • Case Study 1 ndash Microscopy
              • Case Study 1 ndash Diagnosis and Therapy
              • Slide Number 105
              • Slide Number 106
              • Slide Number 107
              • Slide Number 108
              • Slide Number 109
              • Slide Number 110
              • Slide Number 111
              • Slide Number 112
              • Slide Number 113
              • Slide Number 114
              • Slide Number 115
              • Slide Number 116
              • Slide Number 117
              • Slide Number 118
              • Slide Number 119
              • Slide Number 120
              • Slide Number 121
              • Slide Number 122
              • Slide Number 123
              • Slide Number 124
              • Slide Number 125
              • DIC Take Home Messages
              • Slide Number 127
              • Slide Number 128

                Physiology of Hemostasis

                Wound Sealing

                EFFRACbreak in vessel

                FIBRINOLYSIS

                clot destruction

                PRIMARYHEMOSTASIS

                PLASMATICCOAGULATION

                strong clot

                wound sealing blood flow plusmn stopped

                The Three Steps of Hemostasis

                Primary Hemostasis Interaction between vessel wall platelets and adhesive proteins platelet clot

                Coagulation Consolidation of the platelet thrombus insoluble fibrin net

                bull Coagulation factors and inhibitors

                Fibrinolysis Clot lysis clot is digested

                bull Fibrinolytic activators and inhibitors

                Vessel Wall

                Intact endothelium non thrombogenic Synthesis of vasodilators (prostacyclin) No reaction either with platelets or factors

                Sub endotheliumTissue Endothelium

                blood

                When a vessel wall is damaged Exposure of the subendothelium Platelet adhesion Initiation of the mechanisms of coagulation and fibrinolysis

                PlateletsFactors

                Sub endotheliumTissue Endothelium

                blood

                Vessel Wall Damage

                Aim is to clog the damaged vessel ( asymp bricks without cement )

                Primary Hemostasis

                Platelet Structure UnactivatedActivated

                GpIb-IX-V

                GpIIb-IIIa

                α granules (raw materials)PF4 β-TG Fibrinogen VWF Factor V and PAI-1

                dense granules (energy and glue)ATP ADP SerotoninCa2+ Mg2+ P

                Hillman Robert S Ault Kenneth A Rinder Henry M Hematology in Clinical Practice 4th Edition McGraw-Hill New York NY 2005

                Primary Hemostasis

                2) activation2nd shape changeamp release

                platelet at rest 1) adhesion1st shape change

                3) aggregation(not reversible)

                Vasoconstriction occurs first

                Platelets then aggregate on the break in the vessel wall

                Primary Hemostasis AssaysRoutine Platelet count PT APTT TT

                Follow-up von Willebrand Factor Antigen determination Activity Factor VIII PFA-100 Platelet aggregation studies

                SpecializedSend Out Activation markers (b-TG PF4 GPV) Specialized tests for platelet function

                Aim is to strengthen the platelet plug

                Coagulation

                Coagulation is a balancebetween pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis

                THROMBIN

                Fibrinogen Fibrin

                bull Triggering agentsbull pro-enzyme enzyme (serine-protease FIIa FVIIa FIXa FXa)bull Cofactors (FVa amp FVIIIa)

                bull Serine-protease inhibitor Antithrombin (AT) bull Cofactorsinhibitors Protein C Sbull Tissue factor pathway inhibitor (TFPI)

                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                Coagulation Cascade Schematic

                Coagulation factors

                Historic name

                Fibrinogen

                Prothrombin

                Proaccelerin

                Proconvertin

                Anti-hemophilic factor A

                Anti-hemophilic factor B

                Stuart factor

                Rosenthal factor

                Hageman factor

                Fibrin Stabilizing Factor

                Factor

                I

                II

                V

                VII

                VIII

                IX

                X

                XI

                XII

                XIII

                Function

                Substrate

                Pro-enzyme

                Pro-cofactor

                Pro-enzyme

                Pro-cofactor

                Pro-enzyme

                Pro-enzyme

                Pro-enzyme

                Pro-enzyme

                Pro-enzyme

                Pro-enzyme = Zymogen activation Active Enzyme

                Coagulation Assay Mechanisms

                aPTT Based

                PT Based

                PT Based

                Fibrin Under Microscope

                Weisel JW Structure of fibrin impact on clot stability J Thromb Haemost 2007 5 Suppl 1 116-24

                Low thrombin concentration

                High thrombin concentration

                Fibrin Formation

                Soluble FibrinPolymer

                ThrombinFibrinogen

                FM+ fibrinopeptides A amp B

                Stabilized Fibrin clot(not soluble)

                ThrombinXIII XIIIa

                (Digestion of Fibrin)

                Fibrinolysis

                Fibrinolysis Overview

                Destroys fibrin fibers

                Destroys the scab (dried wound)

                Maintains vessel integrity

                Fibrinolysis Overview

                Fibrin =cement fibers

                Plasmin

                Plasmin digests fibrin

                t-PA

                Pro Urokinase

                Urokinase

                PAI-1PAI-1

                Plasminogen Plasmin

                1st Step

                2nd Step

                Fibrinolysis Cascade

                t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin

                Extrinsic pathway(endothelia l cells)

                Intrinsic pathway(plasma)

                Fibrin clot

                D-dimerFibrin degradation products

                Fibrin

                TAFIa

                APAntiplasmin(amp a2-MG)

                PK Kallikrein

                XII

                Fibrinolysis Releases D-dimers

                D-dimer presence fibrin has been formed and digested in patients body

                Normal D-dimer level no thrombosis occurred in the patient

                Basic Pathophysiology of DIC

                Disseminated Intravascular Coagulation (DIC)

                Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management

                Clinical Manifestations of DICOrgan Ischemic Hemorrhagic

                Skin Pupura Fulminans Petechiae

                Gangrene Echymoses

                Acral cyanosis Oozing

                CNS Deliriumcoma Intracranial

                Infarcts Bleeding

                Renal OliguriaAzotemia Hematuria

                Cortical Necrosis

                Cardiovascular Myocardial dysfunction

                Pulmonary DyspneaHypoxia Hemorrhagic lung

                Infarct

                Gastrointestinal Ulcers infarcts Massive hemorrhage

                Endocrine Adrenal infarcts

                Purpura Fulminans with DIC Due to Meningococcal Sepsis

                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                Clinical Conditions Associated With DIC

                Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                Frequency of DIC in Selected Disease States

                Disease Frequency

                Gram-negative sepsis 30-50

                Severe trauma and systemic inflammation 50-70

                Metastasized tumors 15

                Abruptio placentaamniotic fluid embolism 50

                Severe preeclampsia 7

                Giant hemangioma 25

                Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017

                Underlying Diseases in DIC Patients

                In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively

                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                Epidemiology of DIC

                Impact of DIC Status on Mortality - 1

                Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8

                Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC

                Impact of DIC Status on Mortality - 2

                Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients

                Impact of Age on Mortality in DIC Patients

                Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)

                Pathophysiology of DIC

                Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                Pathogenesis of DIC in Sepsis

                Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15

                Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC

                Host Response in Severe Sepsis

                Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral

                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                Organ Failure in Severe Sepsis

                Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure

                Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51

                Mechanism of DIC in Organ Failure

                Underlying condition(sepsis trauma)

                Cytokines

                TF-mediatedactivation of coagulation

                Depression of inhibitory systems

                Reducesfibrinolysis

                Fibrin deposition

                Organ failure

                Inadequate fibrin removal

                Fibrinformation

                Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )

                Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705

                Interaction of Inflammation and Coagulation in Sepsis

                Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines

                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                Mechanism of Multiple Organ Failure in DIC

                Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

                Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

                lipopolysaccharides

                cytokines

                coagulation activation

                mononuclear cell

                tissue factor

                Diverse and Opposing Effects of Thrombin

                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                Coagulation and Fibrinolysis in DIC

                Soluble fibrin Polymer

                XIIIa

                D-Dimer

                E

                Fibrin clot

                Fibrin Degradation Products

                Fibrinogen Thrombin

                Fibrinogen Degradation

                Products

                D E

                Plasmin

                DFM + fibrinopeptides

                Soluble FM ComplexesPre-throm

                boticPost-throm

                botic

                Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

                Mechanism of DIC

                THROMBOSIS

                Fibrin

                Blood activationEndothelial lysisTF expression

                BLEEDING

                FDPs

                D-Dimer

                Plasmin

                Pathophysiology of DIC

                1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

                thromboplastin influx of activated cells (monocytes macrophages)

                Results in an intravascular deposition of fibrin

                Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

                Second step Consumption and depletion of coagulation factors inhibitors (Protein C

                Protein S AT) and platelets Local fibrinolytic response

                bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

                FDP and D-Dimer

                Bleeding

                Pathophysiology of DIC - Mechanism

                Systemic activation of coagulation

                Intravasculardepositionof fibrin

                Thrombosis of small and midsize vessels

                and organ failure

                Depletion of platelets and

                coagulation factors

                Bleeding

                Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                Pathophysiology of DIC ndash 2 Types of Clinical pictures

                Chronic = non - overt DICMay be unrecognized clinically

                Acute = overt DIClife threatening bleedingor multiple organ failure

                Sub-Acute and Non-Overt DIC Clinical Findings

                Compensated non-overt DIC Steady low level or intermittent activation

                bull Compensated by increased production of coagulation components and platelets

                Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                Risk of decompensation leading to overt DIC

                Pathophysiology of Overt DIC

                Massive activation of coagulation and fibrinolysis

                Does not allow for compensatory efforts

                Rapid depletion of coagulation factors inhibitors and platelets

                Thrombosis multiple organ failures

                Bleeding complications and shock

                Physiopathology of DIC ndash Overt DIC Findings

                Thrombin generation

                Thrombosis

                Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                Plasmin generationHemorrhage

                bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                bull Tachycardia hypotension edema

                Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                Pathogenesis Pathways in DIC

                Cytokines

                TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                fibrin inadequateformation fibrin removal

                Fibrin deposition

                Inflammation

                Coagulation

                Stago Celebrates Lab Week 2017

                NA

                Stago 247 Educational Webinar Sites

                wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                Stago Educational Apps

                HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                BREAK

                Diagnostic and Management Approach for DIC

                Diagnosis of DIC

                Clinical diagnosis is obvious in cases of overt DIC

                Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                Lab Diagnosis of DIC ndash Markers of Factor Consumption

                Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                Important to recognize simultaneous formation of thrombin and plasmin

                Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                Lab Diagnosis of DIC ndash Screening Tests

                Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                fibrinogen level) repeat testing assesses progression

                Screening tests not clinically specific or sensitive for DIC

                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                Laboratory Changes in Overt DIC

                DIC Diagnostic Practices Over Time

                Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                British Journal of Haematology Overt DIC Score

                Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                ISTH Step by Step DIC Algorithm

                Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                US Based Validation of ISTH DIC Score

                When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                Differential Diagnosis in DIC

                aHUS atypical hemolytic uremic syndrome

                HUS hemolytic uremic syndrome

                HIT heparin-induced thrombocytopenia

                ITP immune thrombocytopenic purpura

                TTP thrombotic thrombocytopenic purpura

                DIC and MAHA

                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                DIC Management Goals

                Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                DIC Management and Treatment

                Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                DIC Management Strategies

                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                Anticoagulant Factor Concentrate Treatment

                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                Anticoagulant Factor Concentrate Treatment Trials

                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                Markers of Thrombin amp Plasmin Generation in DIC

                D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                Cut-off value

                Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                degradation products Sensitive assay typically with cutoff adapted for DIC

                D-dimer FDPs and DIC

                D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                Follow Up of DIC State of Disease

                Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                FMD-Dimer in DIC Major Differences

                onset of thrombosis

                days

                Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                of Abnormal Results in Patients with Confirmed and Suspected DIC

                0

                20

                40

                60

                80

                100

                94 85 90N = 62

                Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                Positivity of Test Results ISTH Score and Disease State

                Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                Red bar positive for 2 points of DIC score

                Pink bar positive for 1-2 points of DIC score

                HT hematopoietic tumor

                IF infection

                SC solid cancer

                Markers in Patients with or without DIC

                Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                HT hematopoietic tumorIF infectionSC solid cancer

                Comparing an Automated FM vs Manual FSP Test

                Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                Automated (Mitsubishi) vs Automated (Stago)

                In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                Diagnostic Performance of FM and D-dimer in DIC

                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                Diagnostic Performance of FM and D-dimer in DIC

                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                Diagnostic Performance of FM and D-dimer in DIC

                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                Diagnostic Performance of FM and D-dimer in DIC

                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                Diagnostic Performance of FM and D-dimer in DIC

                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                Diagnostic Performance of FM and D-dimer in DIC

                Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                Diagnostic Performance of FM and D-dimer in DIC

                Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                Non Overt DIC Overt DIC

                AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                Trends in Markers of DIC for Different Patients

                Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                Trends in Markers of DIC for Different Patients

                Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                28 day outcome survival

                28 day outcome death

                Determination of Cutoffs of FM and D-dimer in DIC

                Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                Determination of Cutoffs of FM and D-dimer in DIC

                Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                DIC Case Studies

                Case Study 1 - Presentation

                18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                WBC count 77 KμL 423 ndash 907 x KμL

                RBC count 17 MμL 137 ndash 175 x MμL

                Hemoglobin 67 gdL 137 ndash 175 gdL

                Hematocrit 195 401 ndash 510

                MCV 95 fL 790 ndash 922 fL

                MPV 12 fL 94 ndash 124 fL

                Platelet count 9 KμL 161 ndash 347 KμL

                Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                Lymphocytes monocytes eosinophils basophils all below normal range

                PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                Case Study 1 ndash Microscopy

                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                DIC due to TF release by APL blasts

                Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                Transfusions to replace factors along with platelets and RBCs during APL treatment

                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                Case Study 2 ndash Presentation

                TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                PT 30 sec 113 ndash 146 sec

                APTT 75 sec 25 ndash 34 sec

                D-dimer 078 microgml FEU lt050 microgml FEU

                Fibrinogen 92 mgdl 150-400 mgdl

                pH 728 738 to 742

                PaO2 570 mmHg 80-100 mmHg

                WBC 33 times 103mm3 40-11 times 103mm3

                ALT 111 IUL 0ndash34 IUL

                AST 61 IUL 0ndash34 IUL

                BUN 303 mgdL 08-13 mgdL

                Case Study 2 ndash Lab Results

                Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                Case Study 2 ndash Diagnosis

                60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                Case Study 3 ndash Presentation

                TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                PT 228 sec 113 ndash 146 sec

                APTT 45 sec 25 ndash 34 sec

                D-dimer 080 microgml FEU lt050 microgmL FEU

                Fibrinogen 82 mgdL 150-400 mgdL

                FV Normal 70-120

                FVII Normal 55-170

                FVIII Normal 60-150

                Protein C Normal 70-130

                Hb 134 gdL 14-16 gdL

                WBC 81 times 103mm3 40-11 times 103mm3

                ALT 32 IUL 0ndash34 IUL

                AST 28 IUL 0ndash34 IUL

                BUN 09 mgdL 08-13 mgdL

                Case Study 3 ndash Lab Results

                Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                Case Study 3 ndash Diagnosis and Therapy

                Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                Case Study 4 ndash Presentation

                TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                PT 28 sec 113 ndash 146 sec

                APTT 71 sec 25 ndash 34 sec

                D-dimer 31 microgmL FEU lt050 microgml FEU

                Fibrinogen 92 mgdL 150-400 mgdl

                FV Normal 70-120

                FVII Normal 55-170

                FVIII Normal 60-150

                Protein C Normal 70-130

                Hb 158 gdL 14-16 gdL

                WBC 71 times 103mm3 40-11 times 103mm3

                ALT 60 IUL 0ndash34 IUL

                AST 47 IUL 0ndash34 IUL

                BUN 38 mgdL 08-13 mgdL

                Case Study 4 ndash Lab Results

                Lyme disease with DICProvide antibiotics with supportive measures

                Case Study 4 ndash Diagnosis

                55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                Case Study 5 ndash Presentation

                Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                Case Study 5 ndash Lab Results and Time Course

                Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                TEST RESULT REFERENCE RANGE

                Platelet count 33 x 109L 150-450 x 109L

                PT 215 sec 103 ndash 128 sec

                APTT 44 sec 26 ndash 36 sec

                D-dimer 20 microgmL FEU lt025 microgml FEU

                Fibrinogen 34 mgdL 200-375 mgdl

                FII FV FVIII Low Not reported (NR)

                FVII FIX FX vWF Normal NR

                Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                (D) Illustration demonstrating repair

                Case Study 5 ndash Diagnosis and Treatment

                Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                Case Study 6 ndash Presentation

                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                Case Study 6 ndash Lab Results

                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                PT 63 sec gt control 113 ndash 146 sec

                INR 658 1 ndash 125

                APTT 80 sec gt control 25 ndash 34 sec

                D-dimer gt200 microgmL DDU 02 microgmL DDU

                Urine exam Proteinuria and hematuria 150-400 mgdl

                Albumin 28 gdL NR

                Hb 58 gdL NR

                LDH 1196 UL NR

                SGPT 144 IU NR

                SGOT 88 IU NR

                Bilirubin 32 mgdL NR

                DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                day postop

                Case Study 6 ndash Diagnosis and Treatment

                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                Case Study 6 ndash Discussion

                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                Case Study 7 ndash Presentation

                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                Case Study 7 ndash Presentation

                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                Case Study 7 ndash Lab Results vs Time

                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                Case Study 7 ndash Diagnosis and Treatment

                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                Case Study 7 ndash Diagnosis and Treatment

                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                DIC Take Home Messages

                Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                DIC

                Thank you Questions

                • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                • Learning Objectives
                • Slide Number 3
                • Slide Number 4
                • Slide Number 5
                • Slide Number 6
                • Slide Number 7
                • Slide Number 8
                • Wound Sealing
                • The Three Steps of Hemostasis
                • Vessel Wall
                • Slide Number 12
                • Slide Number 13
                • Platelet Structure UnactivatedActivated
                • Primary Hemostasis
                • Primary Hemostasis Assays
                • Slide Number 17
                • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                • Slide Number 19
                • Coagulation factors
                • Coagulation Assay Mechanisms
                • Slide Number 22
                • Fibrin Formation
                • Slide Number 24
                • Fibrinolysis Overview
                • Fibrinolysis Overview
                • Slide Number 27
                • Fibrinolysis Releases D-dimers
                • Basic Pathophysiology of DIC
                • Disseminated Intravascular Coagulation (DIC)
                • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                • Clinical Conditions Associated With DIC
                • Frequency of DIC in Selected Disease States
                • Underlying Diseases in DIC Patients
                • Slide Number 36
                • Slide Number 37
                • Slide Number 38
                • Slide Number 39
                • Pathophysiology of DIC
                • Pathogenesis of DIC in Sepsis
                • Host Response in Severe Sepsis
                • Organ Failure in Severe Sepsis
                • Mechanism of DIC in Organ Failure
                • Interaction of Inflammation and Coagulation in Sepsis
                • Slide Number 47
                • Diverse and Opposing Effects of Thrombin
                • Coagulation and Fibrinolysis in DIC
                • Mechanism of DIC
                • Pathophysiology of DIC
                • Pathophysiology of DIC - Mechanism
                • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                • Sub-Acute and Non-Overt DIC Clinical Findings
                • Pathophysiology of Overt DIC
                • Physiopathology of DIC ndash Overt DIC Findings
                • Slide Number 57
                • Slide Number 58
                • Slide Number 59
                • Slide Number 60
                • Slide Number 61
                • BREAK
                • Diagnostic and Management Approach for DIC
                • Diagnosis of DIC
                • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                • Lab Diagnosis of DIC ndash Screening Tests
                • Slide Number 67
                • Slide Number 68
                • British Journal of Haematology Overt DIC Score
                • Slide Number 70
                • Slide Number 71
                • Slide Number 72
                • Slide Number 73
                • DIC Management Goals
                • DIC Management and Treatment
                • DIC Management Strategies
                • Anticoagulant Factor Concentrate Treatment
                • Anticoagulant Factor Concentrate Treatment Trials
                • Markers of Thrombin amp Plasmin Generation in DIC
                • D-dimer FDPs and DIC
                • D-Dimer and FDPs in DIC
                • Follow Up of DIC State of Disease
                • FMD-Dimer in DIC Major Differences
                • of Abnormal Results in Patients with Confirmed and Suspected DIC
                • Slide Number 85
                • Slide Number 86
                • Comparing an Automated FM vs Manual FSP Test
                • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                • Diagnostic Performance of FM and D-dimer in DIC
                • Diagnostic Performance of FM and D-dimer in DIC
                • Diagnostic Performance of FM and D-dimer in DIC
                • Diagnostic Performance of FM and D-dimer in DIC
                • Diagnostic Performance of FM and D-dimer in DIC
                • Slide Number 94
                • Slide Number 95
                • Slide Number 96
                • Slide Number 97
                • Slide Number 98
                • Slide Number 99
                • DIC Case Studies
                • Case Study 1 - Presentation
                • Case Study 1 ndash Lab Results
                • Case Study 1 ndash Microscopy
                • Case Study 1 ndash Diagnosis and Therapy
                • Slide Number 105
                • Slide Number 106
                • Slide Number 107
                • Slide Number 108
                • Slide Number 109
                • Slide Number 110
                • Slide Number 111
                • Slide Number 112
                • Slide Number 113
                • Slide Number 114
                • Slide Number 115
                • Slide Number 116
                • Slide Number 117
                • Slide Number 118
                • Slide Number 119
                • Slide Number 120
                • Slide Number 121
                • Slide Number 122
                • Slide Number 123
                • Slide Number 124
                • Slide Number 125
                • DIC Take Home Messages
                • Slide Number 127
                • Slide Number 128

                  Wound Sealing

                  EFFRACbreak in vessel

                  FIBRINOLYSIS

                  clot destruction

                  PRIMARYHEMOSTASIS

                  PLASMATICCOAGULATION

                  strong clot

                  wound sealing blood flow plusmn stopped

                  The Three Steps of Hemostasis

                  Primary Hemostasis Interaction between vessel wall platelets and adhesive proteins platelet clot

                  Coagulation Consolidation of the platelet thrombus insoluble fibrin net

                  bull Coagulation factors and inhibitors

                  Fibrinolysis Clot lysis clot is digested

                  bull Fibrinolytic activators and inhibitors

                  Vessel Wall

                  Intact endothelium non thrombogenic Synthesis of vasodilators (prostacyclin) No reaction either with platelets or factors

                  Sub endotheliumTissue Endothelium

                  blood

                  When a vessel wall is damaged Exposure of the subendothelium Platelet adhesion Initiation of the mechanisms of coagulation and fibrinolysis

                  PlateletsFactors

                  Sub endotheliumTissue Endothelium

                  blood

                  Vessel Wall Damage

                  Aim is to clog the damaged vessel ( asymp bricks without cement )

                  Primary Hemostasis

                  Platelet Structure UnactivatedActivated

                  GpIb-IX-V

                  GpIIb-IIIa

                  α granules (raw materials)PF4 β-TG Fibrinogen VWF Factor V and PAI-1

                  dense granules (energy and glue)ATP ADP SerotoninCa2+ Mg2+ P

                  Hillman Robert S Ault Kenneth A Rinder Henry M Hematology in Clinical Practice 4th Edition McGraw-Hill New York NY 2005

                  Primary Hemostasis

                  2) activation2nd shape changeamp release

                  platelet at rest 1) adhesion1st shape change

                  3) aggregation(not reversible)

                  Vasoconstriction occurs first

                  Platelets then aggregate on the break in the vessel wall

                  Primary Hemostasis AssaysRoutine Platelet count PT APTT TT

                  Follow-up von Willebrand Factor Antigen determination Activity Factor VIII PFA-100 Platelet aggregation studies

                  SpecializedSend Out Activation markers (b-TG PF4 GPV) Specialized tests for platelet function

                  Aim is to strengthen the platelet plug

                  Coagulation

                  Coagulation is a balancebetween pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis

                  THROMBIN

                  Fibrinogen Fibrin

                  bull Triggering agentsbull pro-enzyme enzyme (serine-protease FIIa FVIIa FIXa FXa)bull Cofactors (FVa amp FVIIIa)

                  bull Serine-protease inhibitor Antithrombin (AT) bull Cofactorsinhibitors Protein C Sbull Tissue factor pathway inhibitor (TFPI)

                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                  Coagulation Cascade Schematic

                  Coagulation factors

                  Historic name

                  Fibrinogen

                  Prothrombin

                  Proaccelerin

                  Proconvertin

                  Anti-hemophilic factor A

                  Anti-hemophilic factor B

                  Stuart factor

                  Rosenthal factor

                  Hageman factor

                  Fibrin Stabilizing Factor

                  Factor

                  I

                  II

                  V

                  VII

                  VIII

                  IX

                  X

                  XI

                  XII

                  XIII

                  Function

                  Substrate

                  Pro-enzyme

                  Pro-cofactor

                  Pro-enzyme

                  Pro-cofactor

                  Pro-enzyme

                  Pro-enzyme

                  Pro-enzyme

                  Pro-enzyme

                  Pro-enzyme

                  Pro-enzyme = Zymogen activation Active Enzyme

                  Coagulation Assay Mechanisms

                  aPTT Based

                  PT Based

                  PT Based

                  Fibrin Under Microscope

                  Weisel JW Structure of fibrin impact on clot stability J Thromb Haemost 2007 5 Suppl 1 116-24

                  Low thrombin concentration

                  High thrombin concentration

                  Fibrin Formation

                  Soluble FibrinPolymer

                  ThrombinFibrinogen

                  FM+ fibrinopeptides A amp B

                  Stabilized Fibrin clot(not soluble)

                  ThrombinXIII XIIIa

                  (Digestion of Fibrin)

                  Fibrinolysis

                  Fibrinolysis Overview

                  Destroys fibrin fibers

                  Destroys the scab (dried wound)

                  Maintains vessel integrity

                  Fibrinolysis Overview

                  Fibrin =cement fibers

                  Plasmin

                  Plasmin digests fibrin

                  t-PA

                  Pro Urokinase

                  Urokinase

                  PAI-1PAI-1

                  Plasminogen Plasmin

                  1st Step

                  2nd Step

                  Fibrinolysis Cascade

                  t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin

                  Extrinsic pathway(endothelia l cells)

                  Intrinsic pathway(plasma)

                  Fibrin clot

                  D-dimerFibrin degradation products

                  Fibrin

                  TAFIa

                  APAntiplasmin(amp a2-MG)

                  PK Kallikrein

                  XII

                  Fibrinolysis Releases D-dimers

                  D-dimer presence fibrin has been formed and digested in patients body

                  Normal D-dimer level no thrombosis occurred in the patient

                  Basic Pathophysiology of DIC

                  Disseminated Intravascular Coagulation (DIC)

                  Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management

                  Clinical Manifestations of DICOrgan Ischemic Hemorrhagic

                  Skin Pupura Fulminans Petechiae

                  Gangrene Echymoses

                  Acral cyanosis Oozing

                  CNS Deliriumcoma Intracranial

                  Infarcts Bleeding

                  Renal OliguriaAzotemia Hematuria

                  Cortical Necrosis

                  Cardiovascular Myocardial dysfunction

                  Pulmonary DyspneaHypoxia Hemorrhagic lung

                  Infarct

                  Gastrointestinal Ulcers infarcts Massive hemorrhage

                  Endocrine Adrenal infarcts

                  Purpura Fulminans with DIC Due to Meningococcal Sepsis

                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                  Clinical Conditions Associated With DIC

                  Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                  Frequency of DIC in Selected Disease States

                  Disease Frequency

                  Gram-negative sepsis 30-50

                  Severe trauma and systemic inflammation 50-70

                  Metastasized tumors 15

                  Abruptio placentaamniotic fluid embolism 50

                  Severe preeclampsia 7

                  Giant hemangioma 25

                  Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                  Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017

                  Underlying Diseases in DIC Patients

                  In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively

                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                  Epidemiology of DIC

                  Impact of DIC Status on Mortality - 1

                  Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8

                  Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC

                  Impact of DIC Status on Mortality - 2

                  Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                  Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients

                  Impact of Age on Mortality in DIC Patients

                  Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                  Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)

                  Pathophysiology of DIC

                  Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                  Pathogenesis of DIC in Sepsis

                  Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15

                  Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC

                  Host Response in Severe Sepsis

                  Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral

                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                  Organ Failure in Severe Sepsis

                  Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure

                  Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51

                  Mechanism of DIC in Organ Failure

                  Underlying condition(sepsis trauma)

                  Cytokines

                  TF-mediatedactivation of coagulation

                  Depression of inhibitory systems

                  Reducesfibrinolysis

                  Fibrin deposition

                  Organ failure

                  Inadequate fibrin removal

                  Fibrinformation

                  Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )

                  Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705

                  Interaction of Inflammation and Coagulation in Sepsis

                  Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines

                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                  Mechanism of Multiple Organ Failure in DIC

                  Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

                  Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

                  lipopolysaccharides

                  cytokines

                  coagulation activation

                  mononuclear cell

                  tissue factor

                  Diverse and Opposing Effects of Thrombin

                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                  Coagulation and Fibrinolysis in DIC

                  Soluble fibrin Polymer

                  XIIIa

                  D-Dimer

                  E

                  Fibrin clot

                  Fibrin Degradation Products

                  Fibrinogen Thrombin

                  Fibrinogen Degradation

                  Products

                  D E

                  Plasmin

                  DFM + fibrinopeptides

                  Soluble FM ComplexesPre-throm

                  boticPost-throm

                  botic

                  Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

                  Mechanism of DIC

                  THROMBOSIS

                  Fibrin

                  Blood activationEndothelial lysisTF expression

                  BLEEDING

                  FDPs

                  D-Dimer

                  Plasmin

                  Pathophysiology of DIC

                  1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

                  thromboplastin influx of activated cells (monocytes macrophages)

                  Results in an intravascular deposition of fibrin

                  Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

                  Second step Consumption and depletion of coagulation factors inhibitors (Protein C

                  Protein S AT) and platelets Local fibrinolytic response

                  bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

                  FDP and D-Dimer

                  Bleeding

                  Pathophysiology of DIC - Mechanism

                  Systemic activation of coagulation

                  Intravasculardepositionof fibrin

                  Thrombosis of small and midsize vessels

                  and organ failure

                  Depletion of platelets and

                  coagulation factors

                  Bleeding

                  Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                  Pathophysiology of DIC ndash 2 Types of Clinical pictures

                  Chronic = non - overt DICMay be unrecognized clinically

                  Acute = overt DIClife threatening bleedingor multiple organ failure

                  Sub-Acute and Non-Overt DIC Clinical Findings

                  Compensated non-overt DIC Steady low level or intermittent activation

                  bull Compensated by increased production of coagulation components and platelets

                  Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                  Risk of decompensation leading to overt DIC

                  Pathophysiology of Overt DIC

                  Massive activation of coagulation and fibrinolysis

                  Does not allow for compensatory efforts

                  Rapid depletion of coagulation factors inhibitors and platelets

                  Thrombosis multiple organ failures

                  Bleeding complications and shock

                  Physiopathology of DIC ndash Overt DIC Findings

                  Thrombin generation

                  Thrombosis

                  Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                  Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                  Plasmin generationHemorrhage

                  bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                  bull Tachycardia hypotension edema

                  Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                  Pathogenesis Pathways in DIC

                  Cytokines

                  TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                  fibrin inadequateformation fibrin removal

                  Fibrin deposition

                  Inflammation

                  Coagulation

                  Stago Celebrates Lab Week 2017

                  NA

                  Stago 247 Educational Webinar Sites

                  wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                  wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                  Stago Educational Apps

                  HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                  iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                  BREAK

                  Diagnostic and Management Approach for DIC

                  Diagnosis of DIC

                  Clinical diagnosis is obvious in cases of overt DIC

                  Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                  Lab Diagnosis of DIC ndash Markers of Factor Consumption

                  Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                  Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                  Important to recognize simultaneous formation of thrombin and plasmin

                  Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                  Lab Diagnosis of DIC ndash Screening Tests

                  Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                  Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                  fibrinogen level) repeat testing assesses progression

                  Screening tests not clinically specific or sensitive for DIC

                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                  Laboratory Changes in Overt DIC

                  DIC Diagnostic Practices Over Time

                  Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                  British Journal of Haematology Overt DIC Score

                  Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                  ISTH Step by Step DIC Algorithm

                  Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                  US Based Validation of ISTH DIC Score

                  When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                  Differential Diagnosis in DIC

                  aHUS atypical hemolytic uremic syndrome

                  HUS hemolytic uremic syndrome

                  HIT heparin-induced thrombocytopenia

                  ITP immune thrombocytopenic purpura

                  TTP thrombotic thrombocytopenic purpura

                  DIC and MAHA

                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                  lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                  When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                  DIC Management Goals

                  Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                  Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                  DIC Management and Treatment

                  Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                  Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                  requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                  Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                  DIC Management Strategies

                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                  Anticoagulant Factor Concentrate Treatment

                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                  Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                  Anticoagulant Factor Concentrate Treatment Trials

                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                  Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                  Markers of Thrombin amp Plasmin Generation in DIC

                  D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                  Cut-off value

                  Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                  degradation products Sensitive assay typically with cutoff adapted for DIC

                  D-dimer FDPs and DIC

                  D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                  Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                  Follow Up of DIC State of Disease

                  Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                  Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                  FMD-Dimer in DIC Major Differences

                  onset of thrombosis

                  days

                  Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                  FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                  D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                  of Abnormal Results in Patients with Confirmed and Suspected DIC

                  0

                  20

                  40

                  60

                  80

                  100

                  94 85 90N = 62

                  Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                  Positivity of Test Results ISTH Score and Disease State

                  Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                  Red bar positive for 2 points of DIC score

                  Pink bar positive for 1-2 points of DIC score

                  HT hematopoietic tumor

                  IF infection

                  SC solid cancer

                  Markers in Patients with or without DIC

                  Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                  HT hematopoietic tumorIF infectionSC solid cancer

                  Comparing an Automated FM vs Manual FSP Test

                  Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                  Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                  Automated (Mitsubishi) vs Automated (Stago)

                  In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                  Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                  Diagnostic Performance of FM and D-dimer in DIC

                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                  Diagnostic Performance of FM and D-dimer in DIC

                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                  In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                  Diagnostic Performance of FM and D-dimer in DIC

                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                  In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                  Diagnostic Performance of FM and D-dimer in DIC

                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                  In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                  Diagnostic Performance of FM and D-dimer in DIC

                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                  Diagnostic Performance of FM and D-dimer in DIC

                  Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                  No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                  Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                  Diagnostic Performance of FM and D-dimer in DIC

                  Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                  Non Overt DIC Overt DIC

                  AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                  Trends in Markers of DIC for Different Patients

                  Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                  Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                  Trends in Markers of DIC for Different Patients

                  Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                  FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                  28 day outcome survival

                  28 day outcome death

                  Determination of Cutoffs of FM and D-dimer in DIC

                  Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                  Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                  Determination of Cutoffs of FM and D-dimer in DIC

                  Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                  Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                  DIC Case Studies

                  Case Study 1 - Presentation

                  18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                  Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                  WBC count 77 KμL 423 ndash 907 x KμL

                  RBC count 17 MμL 137 ndash 175 x MμL

                  Hemoglobin 67 gdL 137 ndash 175 gdL

                  Hematocrit 195 401 ndash 510

                  MCV 95 fL 790 ndash 922 fL

                  MPV 12 fL 94 ndash 124 fL

                  Platelet count 9 KμL 161 ndash 347 KμL

                  Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                  Lymphocytes monocytes eosinophils basophils all below normal range

                  PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                  APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                  Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                  D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                  Case Study 1 ndash Microscopy

                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                  Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                  Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                  DIC due to TF release by APL blasts

                  Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                  Transfusions to replace factors along with platelets and RBCs during APL treatment

                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                  20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                  Case Study 2 ndash Presentation

                  TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                  PT 30 sec 113 ndash 146 sec

                  APTT 75 sec 25 ndash 34 sec

                  D-dimer 078 microgml FEU lt050 microgml FEU

                  Fibrinogen 92 mgdl 150-400 mgdl

                  pH 728 738 to 742

                  PaO2 570 mmHg 80-100 mmHg

                  WBC 33 times 103mm3 40-11 times 103mm3

                  ALT 111 IUL 0ndash34 IUL

                  AST 61 IUL 0ndash34 IUL

                  BUN 303 mgdL 08-13 mgdL

                  Case Study 2 ndash Lab Results

                  Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                  Case Study 2 ndash Diagnosis

                  60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                  Case Study 3 ndash Presentation

                  TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                  PT 228 sec 113 ndash 146 sec

                  APTT 45 sec 25 ndash 34 sec

                  D-dimer 080 microgml FEU lt050 microgmL FEU

                  Fibrinogen 82 mgdL 150-400 mgdL

                  FV Normal 70-120

                  FVII Normal 55-170

                  FVIII Normal 60-150

                  Protein C Normal 70-130

                  Hb 134 gdL 14-16 gdL

                  WBC 81 times 103mm3 40-11 times 103mm3

                  ALT 32 IUL 0ndash34 IUL

                  AST 28 IUL 0ndash34 IUL

                  BUN 09 mgdL 08-13 mgdL

                  Case Study 3 ndash Lab Results

                  Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                  Case Study 3 ndash Diagnosis and Therapy

                  Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                  Case Study 4 ndash Presentation

                  TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                  PT 28 sec 113 ndash 146 sec

                  APTT 71 sec 25 ndash 34 sec

                  D-dimer 31 microgmL FEU lt050 microgml FEU

                  Fibrinogen 92 mgdL 150-400 mgdl

                  FV Normal 70-120

                  FVII Normal 55-170

                  FVIII Normal 60-150

                  Protein C Normal 70-130

                  Hb 158 gdL 14-16 gdL

                  WBC 71 times 103mm3 40-11 times 103mm3

                  ALT 60 IUL 0ndash34 IUL

                  AST 47 IUL 0ndash34 IUL

                  BUN 38 mgdL 08-13 mgdL

                  Case Study 4 ndash Lab Results

                  Lyme disease with DICProvide antibiotics with supportive measures

                  Case Study 4 ndash Diagnosis

                  55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                  Case Study 5 ndash Presentation

                  Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                  Case Study 5 ndash Lab Results and Time Course

                  Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                  TEST RESULT REFERENCE RANGE

                  Platelet count 33 x 109L 150-450 x 109L

                  PT 215 sec 103 ndash 128 sec

                  APTT 44 sec 26 ndash 36 sec

                  D-dimer 20 microgmL FEU lt025 microgml FEU

                  Fibrinogen 34 mgdL 200-375 mgdl

                  FII FV FVIII Low Not reported (NR)

                  FVII FIX FX vWF Normal NR

                  Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                  DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                  dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                  (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                  (D) Illustration demonstrating repair

                  Case Study 5 ndash Diagnosis and Treatment

                  Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                  29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                  Case Study 6 ndash Presentation

                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                  Case Study 6 ndash Lab Results

                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                  TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                  PT 63 sec gt control 113 ndash 146 sec

                  INR 658 1 ndash 125

                  APTT 80 sec gt control 25 ndash 34 sec

                  D-dimer gt200 microgmL DDU 02 microgmL DDU

                  Urine exam Proteinuria and hematuria 150-400 mgdl

                  Albumin 28 gdL NR

                  Hb 58 gdL NR

                  LDH 1196 UL NR

                  SGPT 144 IU NR

                  SGOT 88 IU NR

                  Bilirubin 32 mgdL NR

                  DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                  day postop

                  Case Study 6 ndash Diagnosis and Treatment

                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                  HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                  Case Study 6 ndash Discussion

                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                  44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                  Case Study 7 ndash Presentation

                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                  On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                  Case Study 7 ndash Presentation

                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                  Case Study 7 ndash Lab Results vs Time

                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                  Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                  Case Study 7 ndash Diagnosis and Treatment

                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                  On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                  Case Study 7 ndash Diagnosis and Treatment

                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                  DIC Take Home Messages

                  Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                  Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                  DIC

                  Thank you Questions

                  • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                  • Learning Objectives
                  • Slide Number 3
                  • Slide Number 4
                  • Slide Number 5
                  • Slide Number 6
                  • Slide Number 7
                  • Slide Number 8
                  • Wound Sealing
                  • The Three Steps of Hemostasis
                  • Vessel Wall
                  • Slide Number 12
                  • Slide Number 13
                  • Platelet Structure UnactivatedActivated
                  • Primary Hemostasis
                  • Primary Hemostasis Assays
                  • Slide Number 17
                  • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                  • Slide Number 19
                  • Coagulation factors
                  • Coagulation Assay Mechanisms
                  • Slide Number 22
                  • Fibrin Formation
                  • Slide Number 24
                  • Fibrinolysis Overview
                  • Fibrinolysis Overview
                  • Slide Number 27
                  • Fibrinolysis Releases D-dimers
                  • Basic Pathophysiology of DIC
                  • Disseminated Intravascular Coagulation (DIC)
                  • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                  • Clinical Conditions Associated With DIC
                  • Frequency of DIC in Selected Disease States
                  • Underlying Diseases in DIC Patients
                  • Slide Number 36
                  • Slide Number 37
                  • Slide Number 38
                  • Slide Number 39
                  • Pathophysiology of DIC
                  • Pathogenesis of DIC in Sepsis
                  • Host Response in Severe Sepsis
                  • Organ Failure in Severe Sepsis
                  • Mechanism of DIC in Organ Failure
                  • Interaction of Inflammation and Coagulation in Sepsis
                  • Slide Number 47
                  • Diverse and Opposing Effects of Thrombin
                  • Coagulation and Fibrinolysis in DIC
                  • Mechanism of DIC
                  • Pathophysiology of DIC
                  • Pathophysiology of DIC - Mechanism
                  • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                  • Sub-Acute and Non-Overt DIC Clinical Findings
                  • Pathophysiology of Overt DIC
                  • Physiopathology of DIC ndash Overt DIC Findings
                  • Slide Number 57
                  • Slide Number 58
                  • Slide Number 59
                  • Slide Number 60
                  • Slide Number 61
                  • BREAK
                  • Diagnostic and Management Approach for DIC
                  • Diagnosis of DIC
                  • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                  • Lab Diagnosis of DIC ndash Screening Tests
                  • Slide Number 67
                  • Slide Number 68
                  • British Journal of Haematology Overt DIC Score
                  • Slide Number 70
                  • Slide Number 71
                  • Slide Number 72
                  • Slide Number 73
                  • DIC Management Goals
                  • DIC Management and Treatment
                  • DIC Management Strategies
                  • Anticoagulant Factor Concentrate Treatment
                  • Anticoagulant Factor Concentrate Treatment Trials
                  • Markers of Thrombin amp Plasmin Generation in DIC
                  • D-dimer FDPs and DIC
                  • D-Dimer and FDPs in DIC
                  • Follow Up of DIC State of Disease
                  • FMD-Dimer in DIC Major Differences
                  • of Abnormal Results in Patients with Confirmed and Suspected DIC
                  • Slide Number 85
                  • Slide Number 86
                  • Comparing an Automated FM vs Manual FSP Test
                  • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                  • Diagnostic Performance of FM and D-dimer in DIC
                  • Diagnostic Performance of FM and D-dimer in DIC
                  • Diagnostic Performance of FM and D-dimer in DIC
                  • Diagnostic Performance of FM and D-dimer in DIC
                  • Diagnostic Performance of FM and D-dimer in DIC
                  • Slide Number 94
                  • Slide Number 95
                  • Slide Number 96
                  • Slide Number 97
                  • Slide Number 98
                  • Slide Number 99
                  • DIC Case Studies
                  • Case Study 1 - Presentation
                  • Case Study 1 ndash Lab Results
                  • Case Study 1 ndash Microscopy
                  • Case Study 1 ndash Diagnosis and Therapy
                  • Slide Number 105
                  • Slide Number 106
                  • Slide Number 107
                  • Slide Number 108
                  • Slide Number 109
                  • Slide Number 110
                  • Slide Number 111
                  • Slide Number 112
                  • Slide Number 113
                  • Slide Number 114
                  • Slide Number 115
                  • Slide Number 116
                  • Slide Number 117
                  • Slide Number 118
                  • Slide Number 119
                  • Slide Number 120
                  • Slide Number 121
                  • Slide Number 122
                  • Slide Number 123
                  • Slide Number 124
                  • Slide Number 125
                  • DIC Take Home Messages
                  • Slide Number 127
                  • Slide Number 128

                    The Three Steps of Hemostasis

                    Primary Hemostasis Interaction between vessel wall platelets and adhesive proteins platelet clot

                    Coagulation Consolidation of the platelet thrombus insoluble fibrin net

                    bull Coagulation factors and inhibitors

                    Fibrinolysis Clot lysis clot is digested

                    bull Fibrinolytic activators and inhibitors

                    Vessel Wall

                    Intact endothelium non thrombogenic Synthesis of vasodilators (prostacyclin) No reaction either with platelets or factors

                    Sub endotheliumTissue Endothelium

                    blood

                    When a vessel wall is damaged Exposure of the subendothelium Platelet adhesion Initiation of the mechanisms of coagulation and fibrinolysis

                    PlateletsFactors

                    Sub endotheliumTissue Endothelium

                    blood

                    Vessel Wall Damage

                    Aim is to clog the damaged vessel ( asymp bricks without cement )

                    Primary Hemostasis

                    Platelet Structure UnactivatedActivated

                    GpIb-IX-V

                    GpIIb-IIIa

                    α granules (raw materials)PF4 β-TG Fibrinogen VWF Factor V and PAI-1

                    dense granules (energy and glue)ATP ADP SerotoninCa2+ Mg2+ P

                    Hillman Robert S Ault Kenneth A Rinder Henry M Hematology in Clinical Practice 4th Edition McGraw-Hill New York NY 2005

                    Primary Hemostasis

                    2) activation2nd shape changeamp release

                    platelet at rest 1) adhesion1st shape change

                    3) aggregation(not reversible)

                    Vasoconstriction occurs first

                    Platelets then aggregate on the break in the vessel wall

                    Primary Hemostasis AssaysRoutine Platelet count PT APTT TT

                    Follow-up von Willebrand Factor Antigen determination Activity Factor VIII PFA-100 Platelet aggregation studies

                    SpecializedSend Out Activation markers (b-TG PF4 GPV) Specialized tests for platelet function

                    Aim is to strengthen the platelet plug

                    Coagulation

                    Coagulation is a balancebetween pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis

                    THROMBIN

                    Fibrinogen Fibrin

                    bull Triggering agentsbull pro-enzyme enzyme (serine-protease FIIa FVIIa FIXa FXa)bull Cofactors (FVa amp FVIIIa)

                    bull Serine-protease inhibitor Antithrombin (AT) bull Cofactorsinhibitors Protein C Sbull Tissue factor pathway inhibitor (TFPI)

                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                    Coagulation Cascade Schematic

                    Coagulation factors

                    Historic name

                    Fibrinogen

                    Prothrombin

                    Proaccelerin

                    Proconvertin

                    Anti-hemophilic factor A

                    Anti-hemophilic factor B

                    Stuart factor

                    Rosenthal factor

                    Hageman factor

                    Fibrin Stabilizing Factor

                    Factor

                    I

                    II

                    V

                    VII

                    VIII

                    IX

                    X

                    XI

                    XII

                    XIII

                    Function

                    Substrate

                    Pro-enzyme

                    Pro-cofactor

                    Pro-enzyme

                    Pro-cofactor

                    Pro-enzyme

                    Pro-enzyme

                    Pro-enzyme

                    Pro-enzyme

                    Pro-enzyme

                    Pro-enzyme = Zymogen activation Active Enzyme

                    Coagulation Assay Mechanisms

                    aPTT Based

                    PT Based

                    PT Based

                    Fibrin Under Microscope

                    Weisel JW Structure of fibrin impact on clot stability J Thromb Haemost 2007 5 Suppl 1 116-24

                    Low thrombin concentration

                    High thrombin concentration

                    Fibrin Formation

                    Soluble FibrinPolymer

                    ThrombinFibrinogen

                    FM+ fibrinopeptides A amp B

                    Stabilized Fibrin clot(not soluble)

                    ThrombinXIII XIIIa

                    (Digestion of Fibrin)

                    Fibrinolysis

                    Fibrinolysis Overview

                    Destroys fibrin fibers

                    Destroys the scab (dried wound)

                    Maintains vessel integrity

                    Fibrinolysis Overview

                    Fibrin =cement fibers

                    Plasmin

                    Plasmin digests fibrin

                    t-PA

                    Pro Urokinase

                    Urokinase

                    PAI-1PAI-1

                    Plasminogen Plasmin

                    1st Step

                    2nd Step

                    Fibrinolysis Cascade

                    t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin

                    Extrinsic pathway(endothelia l cells)

                    Intrinsic pathway(plasma)

                    Fibrin clot

                    D-dimerFibrin degradation products

                    Fibrin

                    TAFIa

                    APAntiplasmin(amp a2-MG)

                    PK Kallikrein

                    XII

                    Fibrinolysis Releases D-dimers

                    D-dimer presence fibrin has been formed and digested in patients body

                    Normal D-dimer level no thrombosis occurred in the patient

                    Basic Pathophysiology of DIC

                    Disseminated Intravascular Coagulation (DIC)

                    Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management

                    Clinical Manifestations of DICOrgan Ischemic Hemorrhagic

                    Skin Pupura Fulminans Petechiae

                    Gangrene Echymoses

                    Acral cyanosis Oozing

                    CNS Deliriumcoma Intracranial

                    Infarcts Bleeding

                    Renal OliguriaAzotemia Hematuria

                    Cortical Necrosis

                    Cardiovascular Myocardial dysfunction

                    Pulmonary DyspneaHypoxia Hemorrhagic lung

                    Infarct

                    Gastrointestinal Ulcers infarcts Massive hemorrhage

                    Endocrine Adrenal infarcts

                    Purpura Fulminans with DIC Due to Meningococcal Sepsis

                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                    Clinical Conditions Associated With DIC

                    Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                    Frequency of DIC in Selected Disease States

                    Disease Frequency

                    Gram-negative sepsis 30-50

                    Severe trauma and systemic inflammation 50-70

                    Metastasized tumors 15

                    Abruptio placentaamniotic fluid embolism 50

                    Severe preeclampsia 7

                    Giant hemangioma 25

                    Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                    Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017

                    Underlying Diseases in DIC Patients

                    In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively

                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                    Epidemiology of DIC

                    Impact of DIC Status on Mortality - 1

                    Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8

                    Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC

                    Impact of DIC Status on Mortality - 2

                    Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                    Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients

                    Impact of Age on Mortality in DIC Patients

                    Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                    Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)

                    Pathophysiology of DIC

                    Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                    Pathogenesis of DIC in Sepsis

                    Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15

                    Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC

                    Host Response in Severe Sepsis

                    Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral

                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                    Organ Failure in Severe Sepsis

                    Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure

                    Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51

                    Mechanism of DIC in Organ Failure

                    Underlying condition(sepsis trauma)

                    Cytokines

                    TF-mediatedactivation of coagulation

                    Depression of inhibitory systems

                    Reducesfibrinolysis

                    Fibrin deposition

                    Organ failure

                    Inadequate fibrin removal

                    Fibrinformation

                    Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )

                    Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705

                    Interaction of Inflammation and Coagulation in Sepsis

                    Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines

                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                    Mechanism of Multiple Organ Failure in DIC

                    Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

                    Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

                    lipopolysaccharides

                    cytokines

                    coagulation activation

                    mononuclear cell

                    tissue factor

                    Diverse and Opposing Effects of Thrombin

                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                    Coagulation and Fibrinolysis in DIC

                    Soluble fibrin Polymer

                    XIIIa

                    D-Dimer

                    E

                    Fibrin clot

                    Fibrin Degradation Products

                    Fibrinogen Thrombin

                    Fibrinogen Degradation

                    Products

                    D E

                    Plasmin

                    DFM + fibrinopeptides

                    Soluble FM ComplexesPre-throm

                    boticPost-throm

                    botic

                    Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

                    Mechanism of DIC

                    THROMBOSIS

                    Fibrin

                    Blood activationEndothelial lysisTF expression

                    BLEEDING

                    FDPs

                    D-Dimer

                    Plasmin

                    Pathophysiology of DIC

                    1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

                    thromboplastin influx of activated cells (monocytes macrophages)

                    Results in an intravascular deposition of fibrin

                    Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

                    Second step Consumption and depletion of coagulation factors inhibitors (Protein C

                    Protein S AT) and platelets Local fibrinolytic response

                    bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

                    FDP and D-Dimer

                    Bleeding

                    Pathophysiology of DIC - Mechanism

                    Systemic activation of coagulation

                    Intravasculardepositionof fibrin

                    Thrombosis of small and midsize vessels

                    and organ failure

                    Depletion of platelets and

                    coagulation factors

                    Bleeding

                    Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                    Pathophysiology of DIC ndash 2 Types of Clinical pictures

                    Chronic = non - overt DICMay be unrecognized clinically

                    Acute = overt DIClife threatening bleedingor multiple organ failure

                    Sub-Acute and Non-Overt DIC Clinical Findings

                    Compensated non-overt DIC Steady low level or intermittent activation

                    bull Compensated by increased production of coagulation components and platelets

                    Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                    Risk of decompensation leading to overt DIC

                    Pathophysiology of Overt DIC

                    Massive activation of coagulation and fibrinolysis

                    Does not allow for compensatory efforts

                    Rapid depletion of coagulation factors inhibitors and platelets

                    Thrombosis multiple organ failures

                    Bleeding complications and shock

                    Physiopathology of DIC ndash Overt DIC Findings

                    Thrombin generation

                    Thrombosis

                    Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                    Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                    Plasmin generationHemorrhage

                    bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                    bull Tachycardia hypotension edema

                    Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                    Pathogenesis Pathways in DIC

                    Cytokines

                    TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                    fibrin inadequateformation fibrin removal

                    Fibrin deposition

                    Inflammation

                    Coagulation

                    Stago Celebrates Lab Week 2017

                    NA

                    Stago 247 Educational Webinar Sites

                    wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                    wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                    Stago Educational Apps

                    HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                    iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                    BREAK

                    Diagnostic and Management Approach for DIC

                    Diagnosis of DIC

                    Clinical diagnosis is obvious in cases of overt DIC

                    Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                    Lab Diagnosis of DIC ndash Markers of Factor Consumption

                    Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                    Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                    Important to recognize simultaneous formation of thrombin and plasmin

                    Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                    Lab Diagnosis of DIC ndash Screening Tests

                    Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                    Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                    fibrinogen level) repeat testing assesses progression

                    Screening tests not clinically specific or sensitive for DIC

                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                    Laboratory Changes in Overt DIC

                    DIC Diagnostic Practices Over Time

                    Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                    British Journal of Haematology Overt DIC Score

                    Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                    ISTH Step by Step DIC Algorithm

                    Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                    US Based Validation of ISTH DIC Score

                    When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                    Differential Diagnosis in DIC

                    aHUS atypical hemolytic uremic syndrome

                    HUS hemolytic uremic syndrome

                    HIT heparin-induced thrombocytopenia

                    ITP immune thrombocytopenic purpura

                    TTP thrombotic thrombocytopenic purpura

                    DIC and MAHA

                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                    lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                    When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                    DIC Management Goals

                    Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                    Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                    DIC Management and Treatment

                    Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                    Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                    requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                    Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                    DIC Management Strategies

                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                    Anticoagulant Factor Concentrate Treatment

                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                    Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                    Anticoagulant Factor Concentrate Treatment Trials

                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                    Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                    Markers of Thrombin amp Plasmin Generation in DIC

                    D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                    Cut-off value

                    Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                    degradation products Sensitive assay typically with cutoff adapted for DIC

                    D-dimer FDPs and DIC

                    D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                    Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                    Follow Up of DIC State of Disease

                    Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                    Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                    FMD-Dimer in DIC Major Differences

                    onset of thrombosis

                    days

                    Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                    FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                    D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                    of Abnormal Results in Patients with Confirmed and Suspected DIC

                    0

                    20

                    40

                    60

                    80

                    100

                    94 85 90N = 62

                    Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                    Positivity of Test Results ISTH Score and Disease State

                    Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                    Red bar positive for 2 points of DIC score

                    Pink bar positive for 1-2 points of DIC score

                    HT hematopoietic tumor

                    IF infection

                    SC solid cancer

                    Markers in Patients with or without DIC

                    Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                    HT hematopoietic tumorIF infectionSC solid cancer

                    Comparing an Automated FM vs Manual FSP Test

                    Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                    Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                    Automated (Mitsubishi) vs Automated (Stago)

                    In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                    Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                    Diagnostic Performance of FM and D-dimer in DIC

                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                    Diagnostic Performance of FM and D-dimer in DIC

                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                    In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                    Diagnostic Performance of FM and D-dimer in DIC

                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                    In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                    Diagnostic Performance of FM and D-dimer in DIC

                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                    In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                    Diagnostic Performance of FM and D-dimer in DIC

                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                    Diagnostic Performance of FM and D-dimer in DIC

                    Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                    No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                    Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                    Diagnostic Performance of FM and D-dimer in DIC

                    Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                    Non Overt DIC Overt DIC

                    AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                    Trends in Markers of DIC for Different Patients

                    Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                    Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                    Trends in Markers of DIC for Different Patients

                    Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                    FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                    28 day outcome survival

                    28 day outcome death

                    Determination of Cutoffs of FM and D-dimer in DIC

                    Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                    Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                    Determination of Cutoffs of FM and D-dimer in DIC

                    Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                    Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                    DIC Case Studies

                    Case Study 1 - Presentation

                    18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                    Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                    WBC count 77 KμL 423 ndash 907 x KμL

                    RBC count 17 MμL 137 ndash 175 x MμL

                    Hemoglobin 67 gdL 137 ndash 175 gdL

                    Hematocrit 195 401 ndash 510

                    MCV 95 fL 790 ndash 922 fL

                    MPV 12 fL 94 ndash 124 fL

                    Platelet count 9 KμL 161 ndash 347 KμL

                    Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                    Lymphocytes monocytes eosinophils basophils all below normal range

                    PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                    APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                    Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                    D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                    Case Study 1 ndash Microscopy

                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                    Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                    Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                    DIC due to TF release by APL blasts

                    Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                    Transfusions to replace factors along with platelets and RBCs during APL treatment

                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                    20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                    Case Study 2 ndash Presentation

                    TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                    PT 30 sec 113 ndash 146 sec

                    APTT 75 sec 25 ndash 34 sec

                    D-dimer 078 microgml FEU lt050 microgml FEU

                    Fibrinogen 92 mgdl 150-400 mgdl

                    pH 728 738 to 742

                    PaO2 570 mmHg 80-100 mmHg

                    WBC 33 times 103mm3 40-11 times 103mm3

                    ALT 111 IUL 0ndash34 IUL

                    AST 61 IUL 0ndash34 IUL

                    BUN 303 mgdL 08-13 mgdL

                    Case Study 2 ndash Lab Results

                    Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                    Case Study 2 ndash Diagnosis

                    60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                    Case Study 3 ndash Presentation

                    TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                    PT 228 sec 113 ndash 146 sec

                    APTT 45 sec 25 ndash 34 sec

                    D-dimer 080 microgml FEU lt050 microgmL FEU

                    Fibrinogen 82 mgdL 150-400 mgdL

                    FV Normal 70-120

                    FVII Normal 55-170

                    FVIII Normal 60-150

                    Protein C Normal 70-130

                    Hb 134 gdL 14-16 gdL

                    WBC 81 times 103mm3 40-11 times 103mm3

                    ALT 32 IUL 0ndash34 IUL

                    AST 28 IUL 0ndash34 IUL

                    BUN 09 mgdL 08-13 mgdL

                    Case Study 3 ndash Lab Results

                    Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                    Case Study 3 ndash Diagnosis and Therapy

                    Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                    Case Study 4 ndash Presentation

                    TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                    PT 28 sec 113 ndash 146 sec

                    APTT 71 sec 25 ndash 34 sec

                    D-dimer 31 microgmL FEU lt050 microgml FEU

                    Fibrinogen 92 mgdL 150-400 mgdl

                    FV Normal 70-120

                    FVII Normal 55-170

                    FVIII Normal 60-150

                    Protein C Normal 70-130

                    Hb 158 gdL 14-16 gdL

                    WBC 71 times 103mm3 40-11 times 103mm3

                    ALT 60 IUL 0ndash34 IUL

                    AST 47 IUL 0ndash34 IUL

                    BUN 38 mgdL 08-13 mgdL

                    Case Study 4 ndash Lab Results

                    Lyme disease with DICProvide antibiotics with supportive measures

                    Case Study 4 ndash Diagnosis

                    55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                    Case Study 5 ndash Presentation

                    Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                    Case Study 5 ndash Lab Results and Time Course

                    Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                    TEST RESULT REFERENCE RANGE

                    Platelet count 33 x 109L 150-450 x 109L

                    PT 215 sec 103 ndash 128 sec

                    APTT 44 sec 26 ndash 36 sec

                    D-dimer 20 microgmL FEU lt025 microgml FEU

                    Fibrinogen 34 mgdL 200-375 mgdl

                    FII FV FVIII Low Not reported (NR)

                    FVII FIX FX vWF Normal NR

                    Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                    DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                    dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                    (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                    (D) Illustration demonstrating repair

                    Case Study 5 ndash Diagnosis and Treatment

                    Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                    29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                    Case Study 6 ndash Presentation

                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                    Case Study 6 ndash Lab Results

                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                    TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                    PT 63 sec gt control 113 ndash 146 sec

                    INR 658 1 ndash 125

                    APTT 80 sec gt control 25 ndash 34 sec

                    D-dimer gt200 microgmL DDU 02 microgmL DDU

                    Urine exam Proteinuria and hematuria 150-400 mgdl

                    Albumin 28 gdL NR

                    Hb 58 gdL NR

                    LDH 1196 UL NR

                    SGPT 144 IU NR

                    SGOT 88 IU NR

                    Bilirubin 32 mgdL NR

                    DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                    day postop

                    Case Study 6 ndash Diagnosis and Treatment

                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                    HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                    Case Study 6 ndash Discussion

                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                    44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                    Case Study 7 ndash Presentation

                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                    On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                    Case Study 7 ndash Presentation

                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                    Case Study 7 ndash Lab Results vs Time

                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                    Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                    Case Study 7 ndash Diagnosis and Treatment

                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                    On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                    Case Study 7 ndash Diagnosis and Treatment

                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                    DIC Take Home Messages

                    Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                    Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                    DIC

                    Thank you Questions

                    • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                    • Learning Objectives
                    • Slide Number 3
                    • Slide Number 4
                    • Slide Number 5
                    • Slide Number 6
                    • Slide Number 7
                    • Slide Number 8
                    • Wound Sealing
                    • The Three Steps of Hemostasis
                    • Vessel Wall
                    • Slide Number 12
                    • Slide Number 13
                    • Platelet Structure UnactivatedActivated
                    • Primary Hemostasis
                    • Primary Hemostasis Assays
                    • Slide Number 17
                    • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                    • Slide Number 19
                    • Coagulation factors
                    • Coagulation Assay Mechanisms
                    • Slide Number 22
                    • Fibrin Formation
                    • Slide Number 24
                    • Fibrinolysis Overview
                    • Fibrinolysis Overview
                    • Slide Number 27
                    • Fibrinolysis Releases D-dimers
                    • Basic Pathophysiology of DIC
                    • Disseminated Intravascular Coagulation (DIC)
                    • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                    • Clinical Conditions Associated With DIC
                    • Frequency of DIC in Selected Disease States
                    • Underlying Diseases in DIC Patients
                    • Slide Number 36
                    • Slide Number 37
                    • Slide Number 38
                    • Slide Number 39
                    • Pathophysiology of DIC
                    • Pathogenesis of DIC in Sepsis
                    • Host Response in Severe Sepsis
                    • Organ Failure in Severe Sepsis
                    • Mechanism of DIC in Organ Failure
                    • Interaction of Inflammation and Coagulation in Sepsis
                    • Slide Number 47
                    • Diverse and Opposing Effects of Thrombin
                    • Coagulation and Fibrinolysis in DIC
                    • Mechanism of DIC
                    • Pathophysiology of DIC
                    • Pathophysiology of DIC - Mechanism
                    • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                    • Sub-Acute and Non-Overt DIC Clinical Findings
                    • Pathophysiology of Overt DIC
                    • Physiopathology of DIC ndash Overt DIC Findings
                    • Slide Number 57
                    • Slide Number 58
                    • Slide Number 59
                    • Slide Number 60
                    • Slide Number 61
                    • BREAK
                    • Diagnostic and Management Approach for DIC
                    • Diagnosis of DIC
                    • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                    • Lab Diagnosis of DIC ndash Screening Tests
                    • Slide Number 67
                    • Slide Number 68
                    • British Journal of Haematology Overt DIC Score
                    • Slide Number 70
                    • Slide Number 71
                    • Slide Number 72
                    • Slide Number 73
                    • DIC Management Goals
                    • DIC Management and Treatment
                    • DIC Management Strategies
                    • Anticoagulant Factor Concentrate Treatment
                    • Anticoagulant Factor Concentrate Treatment Trials
                    • Markers of Thrombin amp Plasmin Generation in DIC
                    • D-dimer FDPs and DIC
                    • D-Dimer and FDPs in DIC
                    • Follow Up of DIC State of Disease
                    • FMD-Dimer in DIC Major Differences
                    • of Abnormal Results in Patients with Confirmed and Suspected DIC
                    • Slide Number 85
                    • Slide Number 86
                    • Comparing an Automated FM vs Manual FSP Test
                    • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                    • Diagnostic Performance of FM and D-dimer in DIC
                    • Diagnostic Performance of FM and D-dimer in DIC
                    • Diagnostic Performance of FM and D-dimer in DIC
                    • Diagnostic Performance of FM and D-dimer in DIC
                    • Diagnostic Performance of FM and D-dimer in DIC
                    • Slide Number 94
                    • Slide Number 95
                    • Slide Number 96
                    • Slide Number 97
                    • Slide Number 98
                    • Slide Number 99
                    • DIC Case Studies
                    • Case Study 1 - Presentation
                    • Case Study 1 ndash Lab Results
                    • Case Study 1 ndash Microscopy
                    • Case Study 1 ndash Diagnosis and Therapy
                    • Slide Number 105
                    • Slide Number 106
                    • Slide Number 107
                    • Slide Number 108
                    • Slide Number 109
                    • Slide Number 110
                    • Slide Number 111
                    • Slide Number 112
                    • Slide Number 113
                    • Slide Number 114
                    • Slide Number 115
                    • Slide Number 116
                    • Slide Number 117
                    • Slide Number 118
                    • Slide Number 119
                    • Slide Number 120
                    • Slide Number 121
                    • Slide Number 122
                    • Slide Number 123
                    • Slide Number 124
                    • Slide Number 125
                    • DIC Take Home Messages
                    • Slide Number 127
                    • Slide Number 128

                      Vessel Wall

                      Intact endothelium non thrombogenic Synthesis of vasodilators (prostacyclin) No reaction either with platelets or factors

                      Sub endotheliumTissue Endothelium

                      blood

                      When a vessel wall is damaged Exposure of the subendothelium Platelet adhesion Initiation of the mechanisms of coagulation and fibrinolysis

                      PlateletsFactors

                      Sub endotheliumTissue Endothelium

                      blood

                      Vessel Wall Damage

                      Aim is to clog the damaged vessel ( asymp bricks without cement )

                      Primary Hemostasis

                      Platelet Structure UnactivatedActivated

                      GpIb-IX-V

                      GpIIb-IIIa

                      α granules (raw materials)PF4 β-TG Fibrinogen VWF Factor V and PAI-1

                      dense granules (energy and glue)ATP ADP SerotoninCa2+ Mg2+ P

                      Hillman Robert S Ault Kenneth A Rinder Henry M Hematology in Clinical Practice 4th Edition McGraw-Hill New York NY 2005

                      Primary Hemostasis

                      2) activation2nd shape changeamp release

                      platelet at rest 1) adhesion1st shape change

                      3) aggregation(not reversible)

                      Vasoconstriction occurs first

                      Platelets then aggregate on the break in the vessel wall

                      Primary Hemostasis AssaysRoutine Platelet count PT APTT TT

                      Follow-up von Willebrand Factor Antigen determination Activity Factor VIII PFA-100 Platelet aggregation studies

                      SpecializedSend Out Activation markers (b-TG PF4 GPV) Specialized tests for platelet function

                      Aim is to strengthen the platelet plug

                      Coagulation

                      Coagulation is a balancebetween pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis

                      THROMBIN

                      Fibrinogen Fibrin

                      bull Triggering agentsbull pro-enzyme enzyme (serine-protease FIIa FVIIa FIXa FXa)bull Cofactors (FVa amp FVIIIa)

                      bull Serine-protease inhibitor Antithrombin (AT) bull Cofactorsinhibitors Protein C Sbull Tissue factor pathway inhibitor (TFPI)

                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                      Coagulation Cascade Schematic

                      Coagulation factors

                      Historic name

                      Fibrinogen

                      Prothrombin

                      Proaccelerin

                      Proconvertin

                      Anti-hemophilic factor A

                      Anti-hemophilic factor B

                      Stuart factor

                      Rosenthal factor

                      Hageman factor

                      Fibrin Stabilizing Factor

                      Factor

                      I

                      II

                      V

                      VII

                      VIII

                      IX

                      X

                      XI

                      XII

                      XIII

                      Function

                      Substrate

                      Pro-enzyme

                      Pro-cofactor

                      Pro-enzyme

                      Pro-cofactor

                      Pro-enzyme

                      Pro-enzyme

                      Pro-enzyme

                      Pro-enzyme

                      Pro-enzyme

                      Pro-enzyme = Zymogen activation Active Enzyme

                      Coagulation Assay Mechanisms

                      aPTT Based

                      PT Based

                      PT Based

                      Fibrin Under Microscope

                      Weisel JW Structure of fibrin impact on clot stability J Thromb Haemost 2007 5 Suppl 1 116-24

                      Low thrombin concentration

                      High thrombin concentration

                      Fibrin Formation

                      Soluble FibrinPolymer

                      ThrombinFibrinogen

                      FM+ fibrinopeptides A amp B

                      Stabilized Fibrin clot(not soluble)

                      ThrombinXIII XIIIa

                      (Digestion of Fibrin)

                      Fibrinolysis

                      Fibrinolysis Overview

                      Destroys fibrin fibers

                      Destroys the scab (dried wound)

                      Maintains vessel integrity

                      Fibrinolysis Overview

                      Fibrin =cement fibers

                      Plasmin

                      Plasmin digests fibrin

                      t-PA

                      Pro Urokinase

                      Urokinase

                      PAI-1PAI-1

                      Plasminogen Plasmin

                      1st Step

                      2nd Step

                      Fibrinolysis Cascade

                      t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin

                      Extrinsic pathway(endothelia l cells)

                      Intrinsic pathway(plasma)

                      Fibrin clot

                      D-dimerFibrin degradation products

                      Fibrin

                      TAFIa

                      APAntiplasmin(amp a2-MG)

                      PK Kallikrein

                      XII

                      Fibrinolysis Releases D-dimers

                      D-dimer presence fibrin has been formed and digested in patients body

                      Normal D-dimer level no thrombosis occurred in the patient

                      Basic Pathophysiology of DIC

                      Disseminated Intravascular Coagulation (DIC)

                      Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management

                      Clinical Manifestations of DICOrgan Ischemic Hemorrhagic

                      Skin Pupura Fulminans Petechiae

                      Gangrene Echymoses

                      Acral cyanosis Oozing

                      CNS Deliriumcoma Intracranial

                      Infarcts Bleeding

                      Renal OliguriaAzotemia Hematuria

                      Cortical Necrosis

                      Cardiovascular Myocardial dysfunction

                      Pulmonary DyspneaHypoxia Hemorrhagic lung

                      Infarct

                      Gastrointestinal Ulcers infarcts Massive hemorrhage

                      Endocrine Adrenal infarcts

                      Purpura Fulminans with DIC Due to Meningococcal Sepsis

                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                      Clinical Conditions Associated With DIC

                      Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                      Frequency of DIC in Selected Disease States

                      Disease Frequency

                      Gram-negative sepsis 30-50

                      Severe trauma and systemic inflammation 50-70

                      Metastasized tumors 15

                      Abruptio placentaamniotic fluid embolism 50

                      Severe preeclampsia 7

                      Giant hemangioma 25

                      Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                      Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017

                      Underlying Diseases in DIC Patients

                      In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively

                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                      Epidemiology of DIC

                      Impact of DIC Status on Mortality - 1

                      Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8

                      Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC

                      Impact of DIC Status on Mortality - 2

                      Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                      Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients

                      Impact of Age on Mortality in DIC Patients

                      Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                      Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)

                      Pathophysiology of DIC

                      Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                      Pathogenesis of DIC in Sepsis

                      Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15

                      Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC

                      Host Response in Severe Sepsis

                      Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral

                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                      Organ Failure in Severe Sepsis

                      Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure

                      Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51

                      Mechanism of DIC in Organ Failure

                      Underlying condition(sepsis trauma)

                      Cytokines

                      TF-mediatedactivation of coagulation

                      Depression of inhibitory systems

                      Reducesfibrinolysis

                      Fibrin deposition

                      Organ failure

                      Inadequate fibrin removal

                      Fibrinformation

                      Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )

                      Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705

                      Interaction of Inflammation and Coagulation in Sepsis

                      Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines

                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                      Mechanism of Multiple Organ Failure in DIC

                      Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

                      Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

                      lipopolysaccharides

                      cytokines

                      coagulation activation

                      mononuclear cell

                      tissue factor

                      Diverse and Opposing Effects of Thrombin

                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                      Coagulation and Fibrinolysis in DIC

                      Soluble fibrin Polymer

                      XIIIa

                      D-Dimer

                      E

                      Fibrin clot

                      Fibrin Degradation Products

                      Fibrinogen Thrombin

                      Fibrinogen Degradation

                      Products

                      D E

                      Plasmin

                      DFM + fibrinopeptides

                      Soluble FM ComplexesPre-throm

                      boticPost-throm

                      botic

                      Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

                      Mechanism of DIC

                      THROMBOSIS

                      Fibrin

                      Blood activationEndothelial lysisTF expression

                      BLEEDING

                      FDPs

                      D-Dimer

                      Plasmin

                      Pathophysiology of DIC

                      1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

                      thromboplastin influx of activated cells (monocytes macrophages)

                      Results in an intravascular deposition of fibrin

                      Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

                      Second step Consumption and depletion of coagulation factors inhibitors (Protein C

                      Protein S AT) and platelets Local fibrinolytic response

                      bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

                      FDP and D-Dimer

                      Bleeding

                      Pathophysiology of DIC - Mechanism

                      Systemic activation of coagulation

                      Intravasculardepositionof fibrin

                      Thrombosis of small and midsize vessels

                      and organ failure

                      Depletion of platelets and

                      coagulation factors

                      Bleeding

                      Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                      Pathophysiology of DIC ndash 2 Types of Clinical pictures

                      Chronic = non - overt DICMay be unrecognized clinically

                      Acute = overt DIClife threatening bleedingor multiple organ failure

                      Sub-Acute and Non-Overt DIC Clinical Findings

                      Compensated non-overt DIC Steady low level or intermittent activation

                      bull Compensated by increased production of coagulation components and platelets

                      Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                      Risk of decompensation leading to overt DIC

                      Pathophysiology of Overt DIC

                      Massive activation of coagulation and fibrinolysis

                      Does not allow for compensatory efforts

                      Rapid depletion of coagulation factors inhibitors and platelets

                      Thrombosis multiple organ failures

                      Bleeding complications and shock

                      Physiopathology of DIC ndash Overt DIC Findings

                      Thrombin generation

                      Thrombosis

                      Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                      Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                      Plasmin generationHemorrhage

                      bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                      bull Tachycardia hypotension edema

                      Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                      Pathogenesis Pathways in DIC

                      Cytokines

                      TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                      fibrin inadequateformation fibrin removal

                      Fibrin deposition

                      Inflammation

                      Coagulation

                      Stago Celebrates Lab Week 2017

                      NA

                      Stago 247 Educational Webinar Sites

                      wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                      wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                      Stago Educational Apps

                      HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                      iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                      BREAK

                      Diagnostic and Management Approach for DIC

                      Diagnosis of DIC

                      Clinical diagnosis is obvious in cases of overt DIC

                      Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                      Lab Diagnosis of DIC ndash Markers of Factor Consumption

                      Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                      Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                      Important to recognize simultaneous formation of thrombin and plasmin

                      Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                      Lab Diagnosis of DIC ndash Screening Tests

                      Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                      Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                      fibrinogen level) repeat testing assesses progression

                      Screening tests not clinically specific or sensitive for DIC

                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                      Laboratory Changes in Overt DIC

                      DIC Diagnostic Practices Over Time

                      Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                      British Journal of Haematology Overt DIC Score

                      Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                      ISTH Step by Step DIC Algorithm

                      Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                      US Based Validation of ISTH DIC Score

                      When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                      Differential Diagnosis in DIC

                      aHUS atypical hemolytic uremic syndrome

                      HUS hemolytic uremic syndrome

                      HIT heparin-induced thrombocytopenia

                      ITP immune thrombocytopenic purpura

                      TTP thrombotic thrombocytopenic purpura

                      DIC and MAHA

                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                      lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                      When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                      DIC Management Goals

                      Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                      Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                      DIC Management and Treatment

                      Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                      Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                      requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                      Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                      DIC Management Strategies

                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                      Anticoagulant Factor Concentrate Treatment

                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                      Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                      Anticoagulant Factor Concentrate Treatment Trials

                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                      Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                      Markers of Thrombin amp Plasmin Generation in DIC

                      D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                      Cut-off value

                      Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                      degradation products Sensitive assay typically with cutoff adapted for DIC

                      D-dimer FDPs and DIC

                      D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                      Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                      Follow Up of DIC State of Disease

                      Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                      Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                      FMD-Dimer in DIC Major Differences

                      onset of thrombosis

                      days

                      Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                      FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                      D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                      of Abnormal Results in Patients with Confirmed and Suspected DIC

                      0

                      20

                      40

                      60

                      80

                      100

                      94 85 90N = 62

                      Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                      Positivity of Test Results ISTH Score and Disease State

                      Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                      Red bar positive for 2 points of DIC score

                      Pink bar positive for 1-2 points of DIC score

                      HT hematopoietic tumor

                      IF infection

                      SC solid cancer

                      Markers in Patients with or without DIC

                      Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                      HT hematopoietic tumorIF infectionSC solid cancer

                      Comparing an Automated FM vs Manual FSP Test

                      Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                      Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                      Automated (Mitsubishi) vs Automated (Stago)

                      In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                      Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                      Diagnostic Performance of FM and D-dimer in DIC

                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                      Diagnostic Performance of FM and D-dimer in DIC

                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                      In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                      Diagnostic Performance of FM and D-dimer in DIC

                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                      In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                      Diagnostic Performance of FM and D-dimer in DIC

                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                      In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                      Diagnostic Performance of FM and D-dimer in DIC

                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                      Diagnostic Performance of FM and D-dimer in DIC

                      Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                      No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                      Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                      Diagnostic Performance of FM and D-dimer in DIC

                      Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                      Non Overt DIC Overt DIC

                      AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                      Trends in Markers of DIC for Different Patients

                      Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                      Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                      Trends in Markers of DIC for Different Patients

                      Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                      FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                      28 day outcome survival

                      28 day outcome death

                      Determination of Cutoffs of FM and D-dimer in DIC

                      Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                      Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                      Determination of Cutoffs of FM and D-dimer in DIC

                      Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                      Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                      DIC Case Studies

                      Case Study 1 - Presentation

                      18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                      Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                      WBC count 77 KμL 423 ndash 907 x KμL

                      RBC count 17 MμL 137 ndash 175 x MμL

                      Hemoglobin 67 gdL 137 ndash 175 gdL

                      Hematocrit 195 401 ndash 510

                      MCV 95 fL 790 ndash 922 fL

                      MPV 12 fL 94 ndash 124 fL

                      Platelet count 9 KμL 161 ndash 347 KμL

                      Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                      Lymphocytes monocytes eosinophils basophils all below normal range

                      PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                      APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                      Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                      D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                      Case Study 1 ndash Microscopy

                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                      Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                      Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                      DIC due to TF release by APL blasts

                      Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                      Transfusions to replace factors along with platelets and RBCs during APL treatment

                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                      20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                      Case Study 2 ndash Presentation

                      TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                      PT 30 sec 113 ndash 146 sec

                      APTT 75 sec 25 ndash 34 sec

                      D-dimer 078 microgml FEU lt050 microgml FEU

                      Fibrinogen 92 mgdl 150-400 mgdl

                      pH 728 738 to 742

                      PaO2 570 mmHg 80-100 mmHg

                      WBC 33 times 103mm3 40-11 times 103mm3

                      ALT 111 IUL 0ndash34 IUL

                      AST 61 IUL 0ndash34 IUL

                      BUN 303 mgdL 08-13 mgdL

                      Case Study 2 ndash Lab Results

                      Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                      Case Study 2 ndash Diagnosis

                      60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                      Case Study 3 ndash Presentation

                      TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                      PT 228 sec 113 ndash 146 sec

                      APTT 45 sec 25 ndash 34 sec

                      D-dimer 080 microgml FEU lt050 microgmL FEU

                      Fibrinogen 82 mgdL 150-400 mgdL

                      FV Normal 70-120

                      FVII Normal 55-170

                      FVIII Normal 60-150

                      Protein C Normal 70-130

                      Hb 134 gdL 14-16 gdL

                      WBC 81 times 103mm3 40-11 times 103mm3

                      ALT 32 IUL 0ndash34 IUL

                      AST 28 IUL 0ndash34 IUL

                      BUN 09 mgdL 08-13 mgdL

                      Case Study 3 ndash Lab Results

                      Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                      Case Study 3 ndash Diagnosis and Therapy

                      Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                      Case Study 4 ndash Presentation

                      TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                      PT 28 sec 113 ndash 146 sec

                      APTT 71 sec 25 ndash 34 sec

                      D-dimer 31 microgmL FEU lt050 microgml FEU

                      Fibrinogen 92 mgdL 150-400 mgdl

                      FV Normal 70-120

                      FVII Normal 55-170

                      FVIII Normal 60-150

                      Protein C Normal 70-130

                      Hb 158 gdL 14-16 gdL

                      WBC 71 times 103mm3 40-11 times 103mm3

                      ALT 60 IUL 0ndash34 IUL

                      AST 47 IUL 0ndash34 IUL

                      BUN 38 mgdL 08-13 mgdL

                      Case Study 4 ndash Lab Results

                      Lyme disease with DICProvide antibiotics with supportive measures

                      Case Study 4 ndash Diagnosis

                      55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                      Case Study 5 ndash Presentation

                      Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                      Case Study 5 ndash Lab Results and Time Course

                      Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                      TEST RESULT REFERENCE RANGE

                      Platelet count 33 x 109L 150-450 x 109L

                      PT 215 sec 103 ndash 128 sec

                      APTT 44 sec 26 ndash 36 sec

                      D-dimer 20 microgmL FEU lt025 microgml FEU

                      Fibrinogen 34 mgdL 200-375 mgdl

                      FII FV FVIII Low Not reported (NR)

                      FVII FIX FX vWF Normal NR

                      Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                      DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                      dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                      (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                      (D) Illustration demonstrating repair

                      Case Study 5 ndash Diagnosis and Treatment

                      Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                      29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                      Case Study 6 ndash Presentation

                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                      Case Study 6 ndash Lab Results

                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                      TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                      PT 63 sec gt control 113 ndash 146 sec

                      INR 658 1 ndash 125

                      APTT 80 sec gt control 25 ndash 34 sec

                      D-dimer gt200 microgmL DDU 02 microgmL DDU

                      Urine exam Proteinuria and hematuria 150-400 mgdl

                      Albumin 28 gdL NR

                      Hb 58 gdL NR

                      LDH 1196 UL NR

                      SGPT 144 IU NR

                      SGOT 88 IU NR

                      Bilirubin 32 mgdL NR

                      DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                      day postop

                      Case Study 6 ndash Diagnosis and Treatment

                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                      HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                      Case Study 6 ndash Discussion

                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                      44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                      Case Study 7 ndash Presentation

                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                      On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                      Case Study 7 ndash Presentation

                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                      Case Study 7 ndash Lab Results vs Time

                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                      Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                      Case Study 7 ndash Diagnosis and Treatment

                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                      On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                      Case Study 7 ndash Diagnosis and Treatment

                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                      DIC Take Home Messages

                      Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                      Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                      DIC

                      Thank you Questions

                      • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                      • Learning Objectives
                      • Slide Number 3
                      • Slide Number 4
                      • Slide Number 5
                      • Slide Number 6
                      • Slide Number 7
                      • Slide Number 8
                      • Wound Sealing
                      • The Three Steps of Hemostasis
                      • Vessel Wall
                      • Slide Number 12
                      • Slide Number 13
                      • Platelet Structure UnactivatedActivated
                      • Primary Hemostasis
                      • Primary Hemostasis Assays
                      • Slide Number 17
                      • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                      • Slide Number 19
                      • Coagulation factors
                      • Coagulation Assay Mechanisms
                      • Slide Number 22
                      • Fibrin Formation
                      • Slide Number 24
                      • Fibrinolysis Overview
                      • Fibrinolysis Overview
                      • Slide Number 27
                      • Fibrinolysis Releases D-dimers
                      • Basic Pathophysiology of DIC
                      • Disseminated Intravascular Coagulation (DIC)
                      • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                      • Clinical Conditions Associated With DIC
                      • Frequency of DIC in Selected Disease States
                      • Underlying Diseases in DIC Patients
                      • Slide Number 36
                      • Slide Number 37
                      • Slide Number 38
                      • Slide Number 39
                      • Pathophysiology of DIC
                      • Pathogenesis of DIC in Sepsis
                      • Host Response in Severe Sepsis
                      • Organ Failure in Severe Sepsis
                      • Mechanism of DIC in Organ Failure
                      • Interaction of Inflammation and Coagulation in Sepsis
                      • Slide Number 47
                      • Diverse and Opposing Effects of Thrombin
                      • Coagulation and Fibrinolysis in DIC
                      • Mechanism of DIC
                      • Pathophysiology of DIC
                      • Pathophysiology of DIC - Mechanism
                      • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                      • Sub-Acute and Non-Overt DIC Clinical Findings
                      • Pathophysiology of Overt DIC
                      • Physiopathology of DIC ndash Overt DIC Findings
                      • Slide Number 57
                      • Slide Number 58
                      • Slide Number 59
                      • Slide Number 60
                      • Slide Number 61
                      • BREAK
                      • Diagnostic and Management Approach for DIC
                      • Diagnosis of DIC
                      • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                      • Lab Diagnosis of DIC ndash Screening Tests
                      • Slide Number 67
                      • Slide Number 68
                      • British Journal of Haematology Overt DIC Score
                      • Slide Number 70
                      • Slide Number 71
                      • Slide Number 72
                      • Slide Number 73
                      • DIC Management Goals
                      • DIC Management and Treatment
                      • DIC Management Strategies
                      • Anticoagulant Factor Concentrate Treatment
                      • Anticoagulant Factor Concentrate Treatment Trials
                      • Markers of Thrombin amp Plasmin Generation in DIC
                      • D-dimer FDPs and DIC
                      • D-Dimer and FDPs in DIC
                      • Follow Up of DIC State of Disease
                      • FMD-Dimer in DIC Major Differences
                      • of Abnormal Results in Patients with Confirmed and Suspected DIC
                      • Slide Number 85
                      • Slide Number 86
                      • Comparing an Automated FM vs Manual FSP Test
                      • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                      • Diagnostic Performance of FM and D-dimer in DIC
                      • Diagnostic Performance of FM and D-dimer in DIC
                      • Diagnostic Performance of FM and D-dimer in DIC
                      • Diagnostic Performance of FM and D-dimer in DIC
                      • Diagnostic Performance of FM and D-dimer in DIC
                      • Slide Number 94
                      • Slide Number 95
                      • Slide Number 96
                      • Slide Number 97
                      • Slide Number 98
                      • Slide Number 99
                      • DIC Case Studies
                      • Case Study 1 - Presentation
                      • Case Study 1 ndash Lab Results
                      • Case Study 1 ndash Microscopy
                      • Case Study 1 ndash Diagnosis and Therapy
                      • Slide Number 105
                      • Slide Number 106
                      • Slide Number 107
                      • Slide Number 108
                      • Slide Number 109
                      • Slide Number 110
                      • Slide Number 111
                      • Slide Number 112
                      • Slide Number 113
                      • Slide Number 114
                      • Slide Number 115
                      • Slide Number 116
                      • Slide Number 117
                      • Slide Number 118
                      • Slide Number 119
                      • Slide Number 120
                      • Slide Number 121
                      • Slide Number 122
                      • Slide Number 123
                      • Slide Number 124
                      • Slide Number 125
                      • DIC Take Home Messages
                      • Slide Number 127
                      • Slide Number 128

                        When a vessel wall is damaged Exposure of the subendothelium Platelet adhesion Initiation of the mechanisms of coagulation and fibrinolysis

                        PlateletsFactors

                        Sub endotheliumTissue Endothelium

                        blood

                        Vessel Wall Damage

                        Aim is to clog the damaged vessel ( asymp bricks without cement )

                        Primary Hemostasis

                        Platelet Structure UnactivatedActivated

                        GpIb-IX-V

                        GpIIb-IIIa

                        α granules (raw materials)PF4 β-TG Fibrinogen VWF Factor V and PAI-1

                        dense granules (energy and glue)ATP ADP SerotoninCa2+ Mg2+ P

                        Hillman Robert S Ault Kenneth A Rinder Henry M Hematology in Clinical Practice 4th Edition McGraw-Hill New York NY 2005

                        Primary Hemostasis

                        2) activation2nd shape changeamp release

                        platelet at rest 1) adhesion1st shape change

                        3) aggregation(not reversible)

                        Vasoconstriction occurs first

                        Platelets then aggregate on the break in the vessel wall

                        Primary Hemostasis AssaysRoutine Platelet count PT APTT TT

                        Follow-up von Willebrand Factor Antigen determination Activity Factor VIII PFA-100 Platelet aggregation studies

                        SpecializedSend Out Activation markers (b-TG PF4 GPV) Specialized tests for platelet function

                        Aim is to strengthen the platelet plug

                        Coagulation

                        Coagulation is a balancebetween pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis

                        THROMBIN

                        Fibrinogen Fibrin

                        bull Triggering agentsbull pro-enzyme enzyme (serine-protease FIIa FVIIa FIXa FXa)bull Cofactors (FVa amp FVIIIa)

                        bull Serine-protease inhibitor Antithrombin (AT) bull Cofactorsinhibitors Protein C Sbull Tissue factor pathway inhibitor (TFPI)

                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                        Coagulation Cascade Schematic

                        Coagulation factors

                        Historic name

                        Fibrinogen

                        Prothrombin

                        Proaccelerin

                        Proconvertin

                        Anti-hemophilic factor A

                        Anti-hemophilic factor B

                        Stuart factor

                        Rosenthal factor

                        Hageman factor

                        Fibrin Stabilizing Factor

                        Factor

                        I

                        II

                        V

                        VII

                        VIII

                        IX

                        X

                        XI

                        XII

                        XIII

                        Function

                        Substrate

                        Pro-enzyme

                        Pro-cofactor

                        Pro-enzyme

                        Pro-cofactor

                        Pro-enzyme

                        Pro-enzyme

                        Pro-enzyme

                        Pro-enzyme

                        Pro-enzyme

                        Pro-enzyme = Zymogen activation Active Enzyme

                        Coagulation Assay Mechanisms

                        aPTT Based

                        PT Based

                        PT Based

                        Fibrin Under Microscope

                        Weisel JW Structure of fibrin impact on clot stability J Thromb Haemost 2007 5 Suppl 1 116-24

                        Low thrombin concentration

                        High thrombin concentration

                        Fibrin Formation

                        Soluble FibrinPolymer

                        ThrombinFibrinogen

                        FM+ fibrinopeptides A amp B

                        Stabilized Fibrin clot(not soluble)

                        ThrombinXIII XIIIa

                        (Digestion of Fibrin)

                        Fibrinolysis

                        Fibrinolysis Overview

                        Destroys fibrin fibers

                        Destroys the scab (dried wound)

                        Maintains vessel integrity

                        Fibrinolysis Overview

                        Fibrin =cement fibers

                        Plasmin

                        Plasmin digests fibrin

                        t-PA

                        Pro Urokinase

                        Urokinase

                        PAI-1PAI-1

                        Plasminogen Plasmin

                        1st Step

                        2nd Step

                        Fibrinolysis Cascade

                        t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin

                        Extrinsic pathway(endothelia l cells)

                        Intrinsic pathway(plasma)

                        Fibrin clot

                        D-dimerFibrin degradation products

                        Fibrin

                        TAFIa

                        APAntiplasmin(amp a2-MG)

                        PK Kallikrein

                        XII

                        Fibrinolysis Releases D-dimers

                        D-dimer presence fibrin has been formed and digested in patients body

                        Normal D-dimer level no thrombosis occurred in the patient

                        Basic Pathophysiology of DIC

                        Disseminated Intravascular Coagulation (DIC)

                        Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management

                        Clinical Manifestations of DICOrgan Ischemic Hemorrhagic

                        Skin Pupura Fulminans Petechiae

                        Gangrene Echymoses

                        Acral cyanosis Oozing

                        CNS Deliriumcoma Intracranial

                        Infarcts Bleeding

                        Renal OliguriaAzotemia Hematuria

                        Cortical Necrosis

                        Cardiovascular Myocardial dysfunction

                        Pulmonary DyspneaHypoxia Hemorrhagic lung

                        Infarct

                        Gastrointestinal Ulcers infarcts Massive hemorrhage

                        Endocrine Adrenal infarcts

                        Purpura Fulminans with DIC Due to Meningococcal Sepsis

                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                        Clinical Conditions Associated With DIC

                        Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                        Frequency of DIC in Selected Disease States

                        Disease Frequency

                        Gram-negative sepsis 30-50

                        Severe trauma and systemic inflammation 50-70

                        Metastasized tumors 15

                        Abruptio placentaamniotic fluid embolism 50

                        Severe preeclampsia 7

                        Giant hemangioma 25

                        Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                        Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017

                        Underlying Diseases in DIC Patients

                        In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively

                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                        Epidemiology of DIC

                        Impact of DIC Status on Mortality - 1

                        Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8

                        Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC

                        Impact of DIC Status on Mortality - 2

                        Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                        Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients

                        Impact of Age on Mortality in DIC Patients

                        Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                        Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)

                        Pathophysiology of DIC

                        Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                        Pathogenesis of DIC in Sepsis

                        Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15

                        Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC

                        Host Response in Severe Sepsis

                        Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral

                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                        Organ Failure in Severe Sepsis

                        Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure

                        Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51

                        Mechanism of DIC in Organ Failure

                        Underlying condition(sepsis trauma)

                        Cytokines

                        TF-mediatedactivation of coagulation

                        Depression of inhibitory systems

                        Reducesfibrinolysis

                        Fibrin deposition

                        Organ failure

                        Inadequate fibrin removal

                        Fibrinformation

                        Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )

                        Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705

                        Interaction of Inflammation and Coagulation in Sepsis

                        Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines

                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                        Mechanism of Multiple Organ Failure in DIC

                        Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

                        Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

                        lipopolysaccharides

                        cytokines

                        coagulation activation

                        mononuclear cell

                        tissue factor

                        Diverse and Opposing Effects of Thrombin

                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                        Coagulation and Fibrinolysis in DIC

                        Soluble fibrin Polymer

                        XIIIa

                        D-Dimer

                        E

                        Fibrin clot

                        Fibrin Degradation Products

                        Fibrinogen Thrombin

                        Fibrinogen Degradation

                        Products

                        D E

                        Plasmin

                        DFM + fibrinopeptides

                        Soluble FM ComplexesPre-throm

                        boticPost-throm

                        botic

                        Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

                        Mechanism of DIC

                        THROMBOSIS

                        Fibrin

                        Blood activationEndothelial lysisTF expression

                        BLEEDING

                        FDPs

                        D-Dimer

                        Plasmin

                        Pathophysiology of DIC

                        1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

                        thromboplastin influx of activated cells (monocytes macrophages)

                        Results in an intravascular deposition of fibrin

                        Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

                        Second step Consumption and depletion of coagulation factors inhibitors (Protein C

                        Protein S AT) and platelets Local fibrinolytic response

                        bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

                        FDP and D-Dimer

                        Bleeding

                        Pathophysiology of DIC - Mechanism

                        Systemic activation of coagulation

                        Intravasculardepositionof fibrin

                        Thrombosis of small and midsize vessels

                        and organ failure

                        Depletion of platelets and

                        coagulation factors

                        Bleeding

                        Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                        Pathophysiology of DIC ndash 2 Types of Clinical pictures

                        Chronic = non - overt DICMay be unrecognized clinically

                        Acute = overt DIClife threatening bleedingor multiple organ failure

                        Sub-Acute and Non-Overt DIC Clinical Findings

                        Compensated non-overt DIC Steady low level or intermittent activation

                        bull Compensated by increased production of coagulation components and platelets

                        Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                        Risk of decompensation leading to overt DIC

                        Pathophysiology of Overt DIC

                        Massive activation of coagulation and fibrinolysis

                        Does not allow for compensatory efforts

                        Rapid depletion of coagulation factors inhibitors and platelets

                        Thrombosis multiple organ failures

                        Bleeding complications and shock

                        Physiopathology of DIC ndash Overt DIC Findings

                        Thrombin generation

                        Thrombosis

                        Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                        Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                        Plasmin generationHemorrhage

                        bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                        bull Tachycardia hypotension edema

                        Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                        Pathogenesis Pathways in DIC

                        Cytokines

                        TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                        fibrin inadequateformation fibrin removal

                        Fibrin deposition

                        Inflammation

                        Coagulation

                        Stago Celebrates Lab Week 2017

                        NA

                        Stago 247 Educational Webinar Sites

                        wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                        wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                        Stago Educational Apps

                        HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                        iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                        BREAK

                        Diagnostic and Management Approach for DIC

                        Diagnosis of DIC

                        Clinical diagnosis is obvious in cases of overt DIC

                        Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                        Lab Diagnosis of DIC ndash Markers of Factor Consumption

                        Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                        Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                        Important to recognize simultaneous formation of thrombin and plasmin

                        Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                        Lab Diagnosis of DIC ndash Screening Tests

                        Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                        Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                        fibrinogen level) repeat testing assesses progression

                        Screening tests not clinically specific or sensitive for DIC

                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                        Laboratory Changes in Overt DIC

                        DIC Diagnostic Practices Over Time

                        Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                        British Journal of Haematology Overt DIC Score

                        Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                        ISTH Step by Step DIC Algorithm

                        Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                        US Based Validation of ISTH DIC Score

                        When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                        Differential Diagnosis in DIC

                        aHUS atypical hemolytic uremic syndrome

                        HUS hemolytic uremic syndrome

                        HIT heparin-induced thrombocytopenia

                        ITP immune thrombocytopenic purpura

                        TTP thrombotic thrombocytopenic purpura

                        DIC and MAHA

                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                        lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                        When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                        DIC Management Goals

                        Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                        Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                        DIC Management and Treatment

                        Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                        Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                        requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                        Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                        DIC Management Strategies

                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                        Anticoagulant Factor Concentrate Treatment

                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                        Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                        Anticoagulant Factor Concentrate Treatment Trials

                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                        Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                        Markers of Thrombin amp Plasmin Generation in DIC

                        D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                        Cut-off value

                        Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                        degradation products Sensitive assay typically with cutoff adapted for DIC

                        D-dimer FDPs and DIC

                        D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                        Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                        Follow Up of DIC State of Disease

                        Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                        Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                        FMD-Dimer in DIC Major Differences

                        onset of thrombosis

                        days

                        Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                        FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                        D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                        of Abnormal Results in Patients with Confirmed and Suspected DIC

                        0

                        20

                        40

                        60

                        80

                        100

                        94 85 90N = 62

                        Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                        Positivity of Test Results ISTH Score and Disease State

                        Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                        Red bar positive for 2 points of DIC score

                        Pink bar positive for 1-2 points of DIC score

                        HT hematopoietic tumor

                        IF infection

                        SC solid cancer

                        Markers in Patients with or without DIC

                        Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                        HT hematopoietic tumorIF infectionSC solid cancer

                        Comparing an Automated FM vs Manual FSP Test

                        Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                        Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                        Automated (Mitsubishi) vs Automated (Stago)

                        In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                        Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                        Diagnostic Performance of FM and D-dimer in DIC

                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                        Diagnostic Performance of FM and D-dimer in DIC

                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                        In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                        Diagnostic Performance of FM and D-dimer in DIC

                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                        In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                        Diagnostic Performance of FM and D-dimer in DIC

                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                        In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                        Diagnostic Performance of FM and D-dimer in DIC

                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                        Diagnostic Performance of FM and D-dimer in DIC

                        Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                        No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                        Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                        Diagnostic Performance of FM and D-dimer in DIC

                        Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                        Non Overt DIC Overt DIC

                        AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                        Trends in Markers of DIC for Different Patients

                        Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                        Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                        Trends in Markers of DIC for Different Patients

                        Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                        FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                        28 day outcome survival

                        28 day outcome death

                        Determination of Cutoffs of FM and D-dimer in DIC

                        Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                        Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                        Determination of Cutoffs of FM and D-dimer in DIC

                        Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                        Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                        DIC Case Studies

                        Case Study 1 - Presentation

                        18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                        Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                        WBC count 77 KμL 423 ndash 907 x KμL

                        RBC count 17 MμL 137 ndash 175 x MμL

                        Hemoglobin 67 gdL 137 ndash 175 gdL

                        Hematocrit 195 401 ndash 510

                        MCV 95 fL 790 ndash 922 fL

                        MPV 12 fL 94 ndash 124 fL

                        Platelet count 9 KμL 161 ndash 347 KμL

                        Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                        Lymphocytes monocytes eosinophils basophils all below normal range

                        PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                        APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                        Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                        D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                        Case Study 1 ndash Microscopy

                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                        Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                        Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                        DIC due to TF release by APL blasts

                        Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                        Transfusions to replace factors along with platelets and RBCs during APL treatment

                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                        20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                        Case Study 2 ndash Presentation

                        TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                        PT 30 sec 113 ndash 146 sec

                        APTT 75 sec 25 ndash 34 sec

                        D-dimer 078 microgml FEU lt050 microgml FEU

                        Fibrinogen 92 mgdl 150-400 mgdl

                        pH 728 738 to 742

                        PaO2 570 mmHg 80-100 mmHg

                        WBC 33 times 103mm3 40-11 times 103mm3

                        ALT 111 IUL 0ndash34 IUL

                        AST 61 IUL 0ndash34 IUL

                        BUN 303 mgdL 08-13 mgdL

                        Case Study 2 ndash Lab Results

                        Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                        Case Study 2 ndash Diagnosis

                        60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                        Case Study 3 ndash Presentation

                        TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                        PT 228 sec 113 ndash 146 sec

                        APTT 45 sec 25 ndash 34 sec

                        D-dimer 080 microgml FEU lt050 microgmL FEU

                        Fibrinogen 82 mgdL 150-400 mgdL

                        FV Normal 70-120

                        FVII Normal 55-170

                        FVIII Normal 60-150

                        Protein C Normal 70-130

                        Hb 134 gdL 14-16 gdL

                        WBC 81 times 103mm3 40-11 times 103mm3

                        ALT 32 IUL 0ndash34 IUL

                        AST 28 IUL 0ndash34 IUL

                        BUN 09 mgdL 08-13 mgdL

                        Case Study 3 ndash Lab Results

                        Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                        Case Study 3 ndash Diagnosis and Therapy

                        Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                        Case Study 4 ndash Presentation

                        TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                        PT 28 sec 113 ndash 146 sec

                        APTT 71 sec 25 ndash 34 sec

                        D-dimer 31 microgmL FEU lt050 microgml FEU

                        Fibrinogen 92 mgdL 150-400 mgdl

                        FV Normal 70-120

                        FVII Normal 55-170

                        FVIII Normal 60-150

                        Protein C Normal 70-130

                        Hb 158 gdL 14-16 gdL

                        WBC 71 times 103mm3 40-11 times 103mm3

                        ALT 60 IUL 0ndash34 IUL

                        AST 47 IUL 0ndash34 IUL

                        BUN 38 mgdL 08-13 mgdL

                        Case Study 4 ndash Lab Results

                        Lyme disease with DICProvide antibiotics with supportive measures

                        Case Study 4 ndash Diagnosis

                        55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                        Case Study 5 ndash Presentation

                        Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                        Case Study 5 ndash Lab Results and Time Course

                        Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                        TEST RESULT REFERENCE RANGE

                        Platelet count 33 x 109L 150-450 x 109L

                        PT 215 sec 103 ndash 128 sec

                        APTT 44 sec 26 ndash 36 sec

                        D-dimer 20 microgmL FEU lt025 microgml FEU

                        Fibrinogen 34 mgdL 200-375 mgdl

                        FII FV FVIII Low Not reported (NR)

                        FVII FIX FX vWF Normal NR

                        Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                        DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                        dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                        (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                        (D) Illustration demonstrating repair

                        Case Study 5 ndash Diagnosis and Treatment

                        Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                        29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                        Case Study 6 ndash Presentation

                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                        Case Study 6 ndash Lab Results

                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                        TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                        PT 63 sec gt control 113 ndash 146 sec

                        INR 658 1 ndash 125

                        APTT 80 sec gt control 25 ndash 34 sec

                        D-dimer gt200 microgmL DDU 02 microgmL DDU

                        Urine exam Proteinuria and hematuria 150-400 mgdl

                        Albumin 28 gdL NR

                        Hb 58 gdL NR

                        LDH 1196 UL NR

                        SGPT 144 IU NR

                        SGOT 88 IU NR

                        Bilirubin 32 mgdL NR

                        DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                        day postop

                        Case Study 6 ndash Diagnosis and Treatment

                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                        HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                        Case Study 6 ndash Discussion

                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                        44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                        Case Study 7 ndash Presentation

                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                        On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                        Case Study 7 ndash Presentation

                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                        Case Study 7 ndash Lab Results vs Time

                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                        Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                        Case Study 7 ndash Diagnosis and Treatment

                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                        On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                        Case Study 7 ndash Diagnosis and Treatment

                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                        DIC Take Home Messages

                        Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                        Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                        DIC

                        Thank you Questions

                        • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                        • Learning Objectives
                        • Slide Number 3
                        • Slide Number 4
                        • Slide Number 5
                        • Slide Number 6
                        • Slide Number 7
                        • Slide Number 8
                        • Wound Sealing
                        • The Three Steps of Hemostasis
                        • Vessel Wall
                        • Slide Number 12
                        • Slide Number 13
                        • Platelet Structure UnactivatedActivated
                        • Primary Hemostasis
                        • Primary Hemostasis Assays
                        • Slide Number 17
                        • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                        • Slide Number 19
                        • Coagulation factors
                        • Coagulation Assay Mechanisms
                        • Slide Number 22
                        • Fibrin Formation
                        • Slide Number 24
                        • Fibrinolysis Overview
                        • Fibrinolysis Overview
                        • Slide Number 27
                        • Fibrinolysis Releases D-dimers
                        • Basic Pathophysiology of DIC
                        • Disseminated Intravascular Coagulation (DIC)
                        • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                        • Clinical Conditions Associated With DIC
                        • Frequency of DIC in Selected Disease States
                        • Underlying Diseases in DIC Patients
                        • Slide Number 36
                        • Slide Number 37
                        • Slide Number 38
                        • Slide Number 39
                        • Pathophysiology of DIC
                        • Pathogenesis of DIC in Sepsis
                        • Host Response in Severe Sepsis
                        • Organ Failure in Severe Sepsis
                        • Mechanism of DIC in Organ Failure
                        • Interaction of Inflammation and Coagulation in Sepsis
                        • Slide Number 47
                        • Diverse and Opposing Effects of Thrombin
                        • Coagulation and Fibrinolysis in DIC
                        • Mechanism of DIC
                        • Pathophysiology of DIC
                        • Pathophysiology of DIC - Mechanism
                        • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                        • Sub-Acute and Non-Overt DIC Clinical Findings
                        • Pathophysiology of Overt DIC
                        • Physiopathology of DIC ndash Overt DIC Findings
                        • Slide Number 57
                        • Slide Number 58
                        • Slide Number 59
                        • Slide Number 60
                        • Slide Number 61
                        • BREAK
                        • Diagnostic and Management Approach for DIC
                        • Diagnosis of DIC
                        • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                        • Lab Diagnosis of DIC ndash Screening Tests
                        • Slide Number 67
                        • Slide Number 68
                        • British Journal of Haematology Overt DIC Score
                        • Slide Number 70
                        • Slide Number 71
                        • Slide Number 72
                        • Slide Number 73
                        • DIC Management Goals
                        • DIC Management and Treatment
                        • DIC Management Strategies
                        • Anticoagulant Factor Concentrate Treatment
                        • Anticoagulant Factor Concentrate Treatment Trials
                        • Markers of Thrombin amp Plasmin Generation in DIC
                        • D-dimer FDPs and DIC
                        • D-Dimer and FDPs in DIC
                        • Follow Up of DIC State of Disease
                        • FMD-Dimer in DIC Major Differences
                        • of Abnormal Results in Patients with Confirmed and Suspected DIC
                        • Slide Number 85
                        • Slide Number 86
                        • Comparing an Automated FM vs Manual FSP Test
                        • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                        • Diagnostic Performance of FM and D-dimer in DIC
                        • Diagnostic Performance of FM and D-dimer in DIC
                        • Diagnostic Performance of FM and D-dimer in DIC
                        • Diagnostic Performance of FM and D-dimer in DIC
                        • Diagnostic Performance of FM and D-dimer in DIC
                        • Slide Number 94
                        • Slide Number 95
                        • Slide Number 96
                        • Slide Number 97
                        • Slide Number 98
                        • Slide Number 99
                        • DIC Case Studies
                        • Case Study 1 - Presentation
                        • Case Study 1 ndash Lab Results
                        • Case Study 1 ndash Microscopy
                        • Case Study 1 ndash Diagnosis and Therapy
                        • Slide Number 105
                        • Slide Number 106
                        • Slide Number 107
                        • Slide Number 108
                        • Slide Number 109
                        • Slide Number 110
                        • Slide Number 111
                        • Slide Number 112
                        • Slide Number 113
                        • Slide Number 114
                        • Slide Number 115
                        • Slide Number 116
                        • Slide Number 117
                        • Slide Number 118
                        • Slide Number 119
                        • Slide Number 120
                        • Slide Number 121
                        • Slide Number 122
                        • Slide Number 123
                        • Slide Number 124
                        • Slide Number 125
                        • DIC Take Home Messages
                        • Slide Number 127
                        • Slide Number 128

                          Aim is to clog the damaged vessel ( asymp bricks without cement )

                          Primary Hemostasis

                          Platelet Structure UnactivatedActivated

                          GpIb-IX-V

                          GpIIb-IIIa

                          α granules (raw materials)PF4 β-TG Fibrinogen VWF Factor V and PAI-1

                          dense granules (energy and glue)ATP ADP SerotoninCa2+ Mg2+ P

                          Hillman Robert S Ault Kenneth A Rinder Henry M Hematology in Clinical Practice 4th Edition McGraw-Hill New York NY 2005

                          Primary Hemostasis

                          2) activation2nd shape changeamp release

                          platelet at rest 1) adhesion1st shape change

                          3) aggregation(not reversible)

                          Vasoconstriction occurs first

                          Platelets then aggregate on the break in the vessel wall

                          Primary Hemostasis AssaysRoutine Platelet count PT APTT TT

                          Follow-up von Willebrand Factor Antigen determination Activity Factor VIII PFA-100 Platelet aggregation studies

                          SpecializedSend Out Activation markers (b-TG PF4 GPV) Specialized tests for platelet function

                          Aim is to strengthen the platelet plug

                          Coagulation

                          Coagulation is a balancebetween pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis

                          THROMBIN

                          Fibrinogen Fibrin

                          bull Triggering agentsbull pro-enzyme enzyme (serine-protease FIIa FVIIa FIXa FXa)bull Cofactors (FVa amp FVIIIa)

                          bull Serine-protease inhibitor Antithrombin (AT) bull Cofactorsinhibitors Protein C Sbull Tissue factor pathway inhibitor (TFPI)

                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                          Coagulation Cascade Schematic

                          Coagulation factors

                          Historic name

                          Fibrinogen

                          Prothrombin

                          Proaccelerin

                          Proconvertin

                          Anti-hemophilic factor A

                          Anti-hemophilic factor B

                          Stuart factor

                          Rosenthal factor

                          Hageman factor

                          Fibrin Stabilizing Factor

                          Factor

                          I

                          II

                          V

                          VII

                          VIII

                          IX

                          X

                          XI

                          XII

                          XIII

                          Function

                          Substrate

                          Pro-enzyme

                          Pro-cofactor

                          Pro-enzyme

                          Pro-cofactor

                          Pro-enzyme

                          Pro-enzyme

                          Pro-enzyme

                          Pro-enzyme

                          Pro-enzyme

                          Pro-enzyme = Zymogen activation Active Enzyme

                          Coagulation Assay Mechanisms

                          aPTT Based

                          PT Based

                          PT Based

                          Fibrin Under Microscope

                          Weisel JW Structure of fibrin impact on clot stability J Thromb Haemost 2007 5 Suppl 1 116-24

                          Low thrombin concentration

                          High thrombin concentration

                          Fibrin Formation

                          Soluble FibrinPolymer

                          ThrombinFibrinogen

                          FM+ fibrinopeptides A amp B

                          Stabilized Fibrin clot(not soluble)

                          ThrombinXIII XIIIa

                          (Digestion of Fibrin)

                          Fibrinolysis

                          Fibrinolysis Overview

                          Destroys fibrin fibers

                          Destroys the scab (dried wound)

                          Maintains vessel integrity

                          Fibrinolysis Overview

                          Fibrin =cement fibers

                          Plasmin

                          Plasmin digests fibrin

                          t-PA

                          Pro Urokinase

                          Urokinase

                          PAI-1PAI-1

                          Plasminogen Plasmin

                          1st Step

                          2nd Step

                          Fibrinolysis Cascade

                          t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin

                          Extrinsic pathway(endothelia l cells)

                          Intrinsic pathway(plasma)

                          Fibrin clot

                          D-dimerFibrin degradation products

                          Fibrin

                          TAFIa

                          APAntiplasmin(amp a2-MG)

                          PK Kallikrein

                          XII

                          Fibrinolysis Releases D-dimers

                          D-dimer presence fibrin has been formed and digested in patients body

                          Normal D-dimer level no thrombosis occurred in the patient

                          Basic Pathophysiology of DIC

                          Disseminated Intravascular Coagulation (DIC)

                          Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management

                          Clinical Manifestations of DICOrgan Ischemic Hemorrhagic

                          Skin Pupura Fulminans Petechiae

                          Gangrene Echymoses

                          Acral cyanosis Oozing

                          CNS Deliriumcoma Intracranial

                          Infarcts Bleeding

                          Renal OliguriaAzotemia Hematuria

                          Cortical Necrosis

                          Cardiovascular Myocardial dysfunction

                          Pulmonary DyspneaHypoxia Hemorrhagic lung

                          Infarct

                          Gastrointestinal Ulcers infarcts Massive hemorrhage

                          Endocrine Adrenal infarcts

                          Purpura Fulminans with DIC Due to Meningococcal Sepsis

                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                          Clinical Conditions Associated With DIC

                          Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                          Frequency of DIC in Selected Disease States

                          Disease Frequency

                          Gram-negative sepsis 30-50

                          Severe trauma and systemic inflammation 50-70

                          Metastasized tumors 15

                          Abruptio placentaamniotic fluid embolism 50

                          Severe preeclampsia 7

                          Giant hemangioma 25

                          Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                          Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017

                          Underlying Diseases in DIC Patients

                          In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively

                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                          Epidemiology of DIC

                          Impact of DIC Status on Mortality - 1

                          Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8

                          Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC

                          Impact of DIC Status on Mortality - 2

                          Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                          Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients

                          Impact of Age on Mortality in DIC Patients

                          Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                          Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)

                          Pathophysiology of DIC

                          Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                          Pathogenesis of DIC in Sepsis

                          Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15

                          Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC

                          Host Response in Severe Sepsis

                          Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral

                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                          Organ Failure in Severe Sepsis

                          Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure

                          Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51

                          Mechanism of DIC in Organ Failure

                          Underlying condition(sepsis trauma)

                          Cytokines

                          TF-mediatedactivation of coagulation

                          Depression of inhibitory systems

                          Reducesfibrinolysis

                          Fibrin deposition

                          Organ failure

                          Inadequate fibrin removal

                          Fibrinformation

                          Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )

                          Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705

                          Interaction of Inflammation and Coagulation in Sepsis

                          Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines

                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                          Mechanism of Multiple Organ Failure in DIC

                          Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

                          Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

                          lipopolysaccharides

                          cytokines

                          coagulation activation

                          mononuclear cell

                          tissue factor

                          Diverse and Opposing Effects of Thrombin

                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                          Coagulation and Fibrinolysis in DIC

                          Soluble fibrin Polymer

                          XIIIa

                          D-Dimer

                          E

                          Fibrin clot

                          Fibrin Degradation Products

                          Fibrinogen Thrombin

                          Fibrinogen Degradation

                          Products

                          D E

                          Plasmin

                          DFM + fibrinopeptides

                          Soluble FM ComplexesPre-throm

                          boticPost-throm

                          botic

                          Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

                          Mechanism of DIC

                          THROMBOSIS

                          Fibrin

                          Blood activationEndothelial lysisTF expression

                          BLEEDING

                          FDPs

                          D-Dimer

                          Plasmin

                          Pathophysiology of DIC

                          1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

                          thromboplastin influx of activated cells (monocytes macrophages)

                          Results in an intravascular deposition of fibrin

                          Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

                          Second step Consumption and depletion of coagulation factors inhibitors (Protein C

                          Protein S AT) and platelets Local fibrinolytic response

                          bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

                          FDP and D-Dimer

                          Bleeding

                          Pathophysiology of DIC - Mechanism

                          Systemic activation of coagulation

                          Intravasculardepositionof fibrin

                          Thrombosis of small and midsize vessels

                          and organ failure

                          Depletion of platelets and

                          coagulation factors

                          Bleeding

                          Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                          Pathophysiology of DIC ndash 2 Types of Clinical pictures

                          Chronic = non - overt DICMay be unrecognized clinically

                          Acute = overt DIClife threatening bleedingor multiple organ failure

                          Sub-Acute and Non-Overt DIC Clinical Findings

                          Compensated non-overt DIC Steady low level or intermittent activation

                          bull Compensated by increased production of coagulation components and platelets

                          Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                          Risk of decompensation leading to overt DIC

                          Pathophysiology of Overt DIC

                          Massive activation of coagulation and fibrinolysis

                          Does not allow for compensatory efforts

                          Rapid depletion of coagulation factors inhibitors and platelets

                          Thrombosis multiple organ failures

                          Bleeding complications and shock

                          Physiopathology of DIC ndash Overt DIC Findings

                          Thrombin generation

                          Thrombosis

                          Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                          Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                          Plasmin generationHemorrhage

                          bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                          bull Tachycardia hypotension edema

                          Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                          Pathogenesis Pathways in DIC

                          Cytokines

                          TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                          fibrin inadequateformation fibrin removal

                          Fibrin deposition

                          Inflammation

                          Coagulation

                          Stago Celebrates Lab Week 2017

                          NA

                          Stago 247 Educational Webinar Sites

                          wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                          wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                          Stago Educational Apps

                          HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                          iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                          BREAK

                          Diagnostic and Management Approach for DIC

                          Diagnosis of DIC

                          Clinical diagnosis is obvious in cases of overt DIC

                          Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                          Lab Diagnosis of DIC ndash Markers of Factor Consumption

                          Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                          Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                          Important to recognize simultaneous formation of thrombin and plasmin

                          Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                          Lab Diagnosis of DIC ndash Screening Tests

                          Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                          Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                          fibrinogen level) repeat testing assesses progression

                          Screening tests not clinically specific or sensitive for DIC

                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                          Laboratory Changes in Overt DIC

                          DIC Diagnostic Practices Over Time

                          Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                          British Journal of Haematology Overt DIC Score

                          Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                          ISTH Step by Step DIC Algorithm

                          Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                          US Based Validation of ISTH DIC Score

                          When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                          Differential Diagnosis in DIC

                          aHUS atypical hemolytic uremic syndrome

                          HUS hemolytic uremic syndrome

                          HIT heparin-induced thrombocytopenia

                          ITP immune thrombocytopenic purpura

                          TTP thrombotic thrombocytopenic purpura

                          DIC and MAHA

                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                          lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                          When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                          DIC Management Goals

                          Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                          Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                          DIC Management and Treatment

                          Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                          Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                          requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                          Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                          DIC Management Strategies

                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                          Anticoagulant Factor Concentrate Treatment

                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                          Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                          Anticoagulant Factor Concentrate Treatment Trials

                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                          Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                          Markers of Thrombin amp Plasmin Generation in DIC

                          D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                          Cut-off value

                          Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                          degradation products Sensitive assay typically with cutoff adapted for DIC

                          D-dimer FDPs and DIC

                          D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                          Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                          Follow Up of DIC State of Disease

                          Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                          Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                          FMD-Dimer in DIC Major Differences

                          onset of thrombosis

                          days

                          Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                          FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                          D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                          of Abnormal Results in Patients with Confirmed and Suspected DIC

                          0

                          20

                          40

                          60

                          80

                          100

                          94 85 90N = 62

                          Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                          Positivity of Test Results ISTH Score and Disease State

                          Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                          Red bar positive for 2 points of DIC score

                          Pink bar positive for 1-2 points of DIC score

                          HT hematopoietic tumor

                          IF infection

                          SC solid cancer

                          Markers in Patients with or without DIC

                          Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                          HT hematopoietic tumorIF infectionSC solid cancer

                          Comparing an Automated FM vs Manual FSP Test

                          Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                          Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                          Automated (Mitsubishi) vs Automated (Stago)

                          In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                          Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                          Diagnostic Performance of FM and D-dimer in DIC

                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                          Diagnostic Performance of FM and D-dimer in DIC

                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                          In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                          Diagnostic Performance of FM and D-dimer in DIC

                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                          In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                          Diagnostic Performance of FM and D-dimer in DIC

                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                          In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                          Diagnostic Performance of FM and D-dimer in DIC

                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                          Diagnostic Performance of FM and D-dimer in DIC

                          Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                          No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                          Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                          Diagnostic Performance of FM and D-dimer in DIC

                          Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                          Non Overt DIC Overt DIC

                          AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                          Trends in Markers of DIC for Different Patients

                          Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                          Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                          Trends in Markers of DIC for Different Patients

                          Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                          FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                          28 day outcome survival

                          28 day outcome death

                          Determination of Cutoffs of FM and D-dimer in DIC

                          Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                          Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                          Determination of Cutoffs of FM and D-dimer in DIC

                          Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                          Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                          DIC Case Studies

                          Case Study 1 - Presentation

                          18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                          Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                          WBC count 77 KμL 423 ndash 907 x KμL

                          RBC count 17 MμL 137 ndash 175 x MμL

                          Hemoglobin 67 gdL 137 ndash 175 gdL

                          Hematocrit 195 401 ndash 510

                          MCV 95 fL 790 ndash 922 fL

                          MPV 12 fL 94 ndash 124 fL

                          Platelet count 9 KμL 161 ndash 347 KμL

                          Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                          Lymphocytes monocytes eosinophils basophils all below normal range

                          PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                          APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                          Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                          D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                          Case Study 1 ndash Microscopy

                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                          Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                          Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                          DIC due to TF release by APL blasts

                          Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                          Transfusions to replace factors along with platelets and RBCs during APL treatment

                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                          20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                          Case Study 2 ndash Presentation

                          TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                          PT 30 sec 113 ndash 146 sec

                          APTT 75 sec 25 ndash 34 sec

                          D-dimer 078 microgml FEU lt050 microgml FEU

                          Fibrinogen 92 mgdl 150-400 mgdl

                          pH 728 738 to 742

                          PaO2 570 mmHg 80-100 mmHg

                          WBC 33 times 103mm3 40-11 times 103mm3

                          ALT 111 IUL 0ndash34 IUL

                          AST 61 IUL 0ndash34 IUL

                          BUN 303 mgdL 08-13 mgdL

                          Case Study 2 ndash Lab Results

                          Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                          Case Study 2 ndash Diagnosis

                          60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                          Case Study 3 ndash Presentation

                          TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                          PT 228 sec 113 ndash 146 sec

                          APTT 45 sec 25 ndash 34 sec

                          D-dimer 080 microgml FEU lt050 microgmL FEU

                          Fibrinogen 82 mgdL 150-400 mgdL

                          FV Normal 70-120

                          FVII Normal 55-170

                          FVIII Normal 60-150

                          Protein C Normal 70-130

                          Hb 134 gdL 14-16 gdL

                          WBC 81 times 103mm3 40-11 times 103mm3

                          ALT 32 IUL 0ndash34 IUL

                          AST 28 IUL 0ndash34 IUL

                          BUN 09 mgdL 08-13 mgdL

                          Case Study 3 ndash Lab Results

                          Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                          Case Study 3 ndash Diagnosis and Therapy

                          Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                          Case Study 4 ndash Presentation

                          TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                          PT 28 sec 113 ndash 146 sec

                          APTT 71 sec 25 ndash 34 sec

                          D-dimer 31 microgmL FEU lt050 microgml FEU

                          Fibrinogen 92 mgdL 150-400 mgdl

                          FV Normal 70-120

                          FVII Normal 55-170

                          FVIII Normal 60-150

                          Protein C Normal 70-130

                          Hb 158 gdL 14-16 gdL

                          WBC 71 times 103mm3 40-11 times 103mm3

                          ALT 60 IUL 0ndash34 IUL

                          AST 47 IUL 0ndash34 IUL

                          BUN 38 mgdL 08-13 mgdL

                          Case Study 4 ndash Lab Results

                          Lyme disease with DICProvide antibiotics with supportive measures

                          Case Study 4 ndash Diagnosis

                          55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                          Case Study 5 ndash Presentation

                          Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                          Case Study 5 ndash Lab Results and Time Course

                          Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                          TEST RESULT REFERENCE RANGE

                          Platelet count 33 x 109L 150-450 x 109L

                          PT 215 sec 103 ndash 128 sec

                          APTT 44 sec 26 ndash 36 sec

                          D-dimer 20 microgmL FEU lt025 microgml FEU

                          Fibrinogen 34 mgdL 200-375 mgdl

                          FII FV FVIII Low Not reported (NR)

                          FVII FIX FX vWF Normal NR

                          Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                          DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                          dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                          (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                          (D) Illustration demonstrating repair

                          Case Study 5 ndash Diagnosis and Treatment

                          Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                          29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                          Case Study 6 ndash Presentation

                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                          Case Study 6 ndash Lab Results

                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                          TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                          PT 63 sec gt control 113 ndash 146 sec

                          INR 658 1 ndash 125

                          APTT 80 sec gt control 25 ndash 34 sec

                          D-dimer gt200 microgmL DDU 02 microgmL DDU

                          Urine exam Proteinuria and hematuria 150-400 mgdl

                          Albumin 28 gdL NR

                          Hb 58 gdL NR

                          LDH 1196 UL NR

                          SGPT 144 IU NR

                          SGOT 88 IU NR

                          Bilirubin 32 mgdL NR

                          DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                          day postop

                          Case Study 6 ndash Diagnosis and Treatment

                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                          HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                          Case Study 6 ndash Discussion

                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                          44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                          Case Study 7 ndash Presentation

                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                          On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                          Case Study 7 ndash Presentation

                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                          Case Study 7 ndash Lab Results vs Time

                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                          Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                          Case Study 7 ndash Diagnosis and Treatment

                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                          On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                          Case Study 7 ndash Diagnosis and Treatment

                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                          DIC Take Home Messages

                          Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                          Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                          DIC

                          Thank you Questions

                          • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                          • Learning Objectives
                          • Slide Number 3
                          • Slide Number 4
                          • Slide Number 5
                          • Slide Number 6
                          • Slide Number 7
                          • Slide Number 8
                          • Wound Sealing
                          • The Three Steps of Hemostasis
                          • Vessel Wall
                          • Slide Number 12
                          • Slide Number 13
                          • Platelet Structure UnactivatedActivated
                          • Primary Hemostasis
                          • Primary Hemostasis Assays
                          • Slide Number 17
                          • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                          • Slide Number 19
                          • Coagulation factors
                          • Coagulation Assay Mechanisms
                          • Slide Number 22
                          • Fibrin Formation
                          • Slide Number 24
                          • Fibrinolysis Overview
                          • Fibrinolysis Overview
                          • Slide Number 27
                          • Fibrinolysis Releases D-dimers
                          • Basic Pathophysiology of DIC
                          • Disseminated Intravascular Coagulation (DIC)
                          • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                          • Clinical Conditions Associated With DIC
                          • Frequency of DIC in Selected Disease States
                          • Underlying Diseases in DIC Patients
                          • Slide Number 36
                          • Slide Number 37
                          • Slide Number 38
                          • Slide Number 39
                          • Pathophysiology of DIC
                          • Pathogenesis of DIC in Sepsis
                          • Host Response in Severe Sepsis
                          • Organ Failure in Severe Sepsis
                          • Mechanism of DIC in Organ Failure
                          • Interaction of Inflammation and Coagulation in Sepsis
                          • Slide Number 47
                          • Diverse and Opposing Effects of Thrombin
                          • Coagulation and Fibrinolysis in DIC
                          • Mechanism of DIC
                          • Pathophysiology of DIC
                          • Pathophysiology of DIC - Mechanism
                          • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                          • Sub-Acute and Non-Overt DIC Clinical Findings
                          • Pathophysiology of Overt DIC
                          • Physiopathology of DIC ndash Overt DIC Findings
                          • Slide Number 57
                          • Slide Number 58
                          • Slide Number 59
                          • Slide Number 60
                          • Slide Number 61
                          • BREAK
                          • Diagnostic and Management Approach for DIC
                          • Diagnosis of DIC
                          • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                          • Lab Diagnosis of DIC ndash Screening Tests
                          • Slide Number 67
                          • Slide Number 68
                          • British Journal of Haematology Overt DIC Score
                          • Slide Number 70
                          • Slide Number 71
                          • Slide Number 72
                          • Slide Number 73
                          • DIC Management Goals
                          • DIC Management and Treatment
                          • DIC Management Strategies
                          • Anticoagulant Factor Concentrate Treatment
                          • Anticoagulant Factor Concentrate Treatment Trials
                          • Markers of Thrombin amp Plasmin Generation in DIC
                          • D-dimer FDPs and DIC
                          • D-Dimer and FDPs in DIC
                          • Follow Up of DIC State of Disease
                          • FMD-Dimer in DIC Major Differences
                          • of Abnormal Results in Patients with Confirmed and Suspected DIC
                          • Slide Number 85
                          • Slide Number 86
                          • Comparing an Automated FM vs Manual FSP Test
                          • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                          • Diagnostic Performance of FM and D-dimer in DIC
                          • Diagnostic Performance of FM and D-dimer in DIC
                          • Diagnostic Performance of FM and D-dimer in DIC
                          • Diagnostic Performance of FM and D-dimer in DIC
                          • Diagnostic Performance of FM and D-dimer in DIC
                          • Slide Number 94
                          • Slide Number 95
                          • Slide Number 96
                          • Slide Number 97
                          • Slide Number 98
                          • Slide Number 99
                          • DIC Case Studies
                          • Case Study 1 - Presentation
                          • Case Study 1 ndash Lab Results
                          • Case Study 1 ndash Microscopy
                          • Case Study 1 ndash Diagnosis and Therapy
                          • Slide Number 105
                          • Slide Number 106
                          • Slide Number 107
                          • Slide Number 108
                          • Slide Number 109
                          • Slide Number 110
                          • Slide Number 111
                          • Slide Number 112
                          • Slide Number 113
                          • Slide Number 114
                          • Slide Number 115
                          • Slide Number 116
                          • Slide Number 117
                          • Slide Number 118
                          • Slide Number 119
                          • Slide Number 120
                          • Slide Number 121
                          • Slide Number 122
                          • Slide Number 123
                          • Slide Number 124
                          • Slide Number 125
                          • DIC Take Home Messages
                          • Slide Number 127
                          • Slide Number 128

                            Platelet Structure UnactivatedActivated

                            GpIb-IX-V

                            GpIIb-IIIa

                            α granules (raw materials)PF4 β-TG Fibrinogen VWF Factor V and PAI-1

                            dense granules (energy and glue)ATP ADP SerotoninCa2+ Mg2+ P

                            Hillman Robert S Ault Kenneth A Rinder Henry M Hematology in Clinical Practice 4th Edition McGraw-Hill New York NY 2005

                            Primary Hemostasis

                            2) activation2nd shape changeamp release

                            platelet at rest 1) adhesion1st shape change

                            3) aggregation(not reversible)

                            Vasoconstriction occurs first

                            Platelets then aggregate on the break in the vessel wall

                            Primary Hemostasis AssaysRoutine Platelet count PT APTT TT

                            Follow-up von Willebrand Factor Antigen determination Activity Factor VIII PFA-100 Platelet aggregation studies

                            SpecializedSend Out Activation markers (b-TG PF4 GPV) Specialized tests for platelet function

                            Aim is to strengthen the platelet plug

                            Coagulation

                            Coagulation is a balancebetween pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis

                            THROMBIN

                            Fibrinogen Fibrin

                            bull Triggering agentsbull pro-enzyme enzyme (serine-protease FIIa FVIIa FIXa FXa)bull Cofactors (FVa amp FVIIIa)

                            bull Serine-protease inhibitor Antithrombin (AT) bull Cofactorsinhibitors Protein C Sbull Tissue factor pathway inhibitor (TFPI)

                            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                            Coagulation Cascade Schematic

                            Coagulation factors

                            Historic name

                            Fibrinogen

                            Prothrombin

                            Proaccelerin

                            Proconvertin

                            Anti-hemophilic factor A

                            Anti-hemophilic factor B

                            Stuart factor

                            Rosenthal factor

                            Hageman factor

                            Fibrin Stabilizing Factor

                            Factor

                            I

                            II

                            V

                            VII

                            VIII

                            IX

                            X

                            XI

                            XII

                            XIII

                            Function

                            Substrate

                            Pro-enzyme

                            Pro-cofactor

                            Pro-enzyme

                            Pro-cofactor

                            Pro-enzyme

                            Pro-enzyme

                            Pro-enzyme

                            Pro-enzyme

                            Pro-enzyme

                            Pro-enzyme = Zymogen activation Active Enzyme

                            Coagulation Assay Mechanisms

                            aPTT Based

                            PT Based

                            PT Based

                            Fibrin Under Microscope

                            Weisel JW Structure of fibrin impact on clot stability J Thromb Haemost 2007 5 Suppl 1 116-24

                            Low thrombin concentration

                            High thrombin concentration

                            Fibrin Formation

                            Soluble FibrinPolymer

                            ThrombinFibrinogen

                            FM+ fibrinopeptides A amp B

                            Stabilized Fibrin clot(not soluble)

                            ThrombinXIII XIIIa

                            (Digestion of Fibrin)

                            Fibrinolysis

                            Fibrinolysis Overview

                            Destroys fibrin fibers

                            Destroys the scab (dried wound)

                            Maintains vessel integrity

                            Fibrinolysis Overview

                            Fibrin =cement fibers

                            Plasmin

                            Plasmin digests fibrin

                            t-PA

                            Pro Urokinase

                            Urokinase

                            PAI-1PAI-1

                            Plasminogen Plasmin

                            1st Step

                            2nd Step

                            Fibrinolysis Cascade

                            t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin

                            Extrinsic pathway(endothelia l cells)

                            Intrinsic pathway(plasma)

                            Fibrin clot

                            D-dimerFibrin degradation products

                            Fibrin

                            TAFIa

                            APAntiplasmin(amp a2-MG)

                            PK Kallikrein

                            XII

                            Fibrinolysis Releases D-dimers

                            D-dimer presence fibrin has been formed and digested in patients body

                            Normal D-dimer level no thrombosis occurred in the patient

                            Basic Pathophysiology of DIC

                            Disseminated Intravascular Coagulation (DIC)

                            Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management

                            Clinical Manifestations of DICOrgan Ischemic Hemorrhagic

                            Skin Pupura Fulminans Petechiae

                            Gangrene Echymoses

                            Acral cyanosis Oozing

                            CNS Deliriumcoma Intracranial

                            Infarcts Bleeding

                            Renal OliguriaAzotemia Hematuria

                            Cortical Necrosis

                            Cardiovascular Myocardial dysfunction

                            Pulmonary DyspneaHypoxia Hemorrhagic lung

                            Infarct

                            Gastrointestinal Ulcers infarcts Massive hemorrhage

                            Endocrine Adrenal infarcts

                            Purpura Fulminans with DIC Due to Meningococcal Sepsis

                            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                            Clinical Conditions Associated With DIC

                            Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                            Frequency of DIC in Selected Disease States

                            Disease Frequency

                            Gram-negative sepsis 30-50

                            Severe trauma and systemic inflammation 50-70

                            Metastasized tumors 15

                            Abruptio placentaamniotic fluid embolism 50

                            Severe preeclampsia 7

                            Giant hemangioma 25

                            Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                            Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017

                            Underlying Diseases in DIC Patients

                            In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively

                            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                            Epidemiology of DIC

                            Impact of DIC Status on Mortality - 1

                            Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8

                            Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC

                            Impact of DIC Status on Mortality - 2

                            Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                            Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients

                            Impact of Age on Mortality in DIC Patients

                            Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                            Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)

                            Pathophysiology of DIC

                            Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                            Pathogenesis of DIC in Sepsis

                            Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15

                            Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC

                            Host Response in Severe Sepsis

                            Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral

                            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                            Organ Failure in Severe Sepsis

                            Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure

                            Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51

                            Mechanism of DIC in Organ Failure

                            Underlying condition(sepsis trauma)

                            Cytokines

                            TF-mediatedactivation of coagulation

                            Depression of inhibitory systems

                            Reducesfibrinolysis

                            Fibrin deposition

                            Organ failure

                            Inadequate fibrin removal

                            Fibrinformation

                            Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )

                            Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705

                            Interaction of Inflammation and Coagulation in Sepsis

                            Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines

                            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                            Mechanism of Multiple Organ Failure in DIC

                            Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

                            Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

                            lipopolysaccharides

                            cytokines

                            coagulation activation

                            mononuclear cell

                            tissue factor

                            Diverse and Opposing Effects of Thrombin

                            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                            Coagulation and Fibrinolysis in DIC

                            Soluble fibrin Polymer

                            XIIIa

                            D-Dimer

                            E

                            Fibrin clot

                            Fibrin Degradation Products

                            Fibrinogen Thrombin

                            Fibrinogen Degradation

                            Products

                            D E

                            Plasmin

                            DFM + fibrinopeptides

                            Soluble FM ComplexesPre-throm

                            boticPost-throm

                            botic

                            Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

                            Mechanism of DIC

                            THROMBOSIS

                            Fibrin

                            Blood activationEndothelial lysisTF expression

                            BLEEDING

                            FDPs

                            D-Dimer

                            Plasmin

                            Pathophysiology of DIC

                            1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

                            thromboplastin influx of activated cells (monocytes macrophages)

                            Results in an intravascular deposition of fibrin

                            Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

                            Second step Consumption and depletion of coagulation factors inhibitors (Protein C

                            Protein S AT) and platelets Local fibrinolytic response

                            bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

                            FDP and D-Dimer

                            Bleeding

                            Pathophysiology of DIC - Mechanism

                            Systemic activation of coagulation

                            Intravasculardepositionof fibrin

                            Thrombosis of small and midsize vessels

                            and organ failure

                            Depletion of platelets and

                            coagulation factors

                            Bleeding

                            Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                            Pathophysiology of DIC ndash 2 Types of Clinical pictures

                            Chronic = non - overt DICMay be unrecognized clinically

                            Acute = overt DIClife threatening bleedingor multiple organ failure

                            Sub-Acute and Non-Overt DIC Clinical Findings

                            Compensated non-overt DIC Steady low level or intermittent activation

                            bull Compensated by increased production of coagulation components and platelets

                            Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                            Risk of decompensation leading to overt DIC

                            Pathophysiology of Overt DIC

                            Massive activation of coagulation and fibrinolysis

                            Does not allow for compensatory efforts

                            Rapid depletion of coagulation factors inhibitors and platelets

                            Thrombosis multiple organ failures

                            Bleeding complications and shock

                            Physiopathology of DIC ndash Overt DIC Findings

                            Thrombin generation

                            Thrombosis

                            Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                            Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                            Plasmin generationHemorrhage

                            bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                            bull Tachycardia hypotension edema

                            Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                            Pathogenesis Pathways in DIC

                            Cytokines

                            TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                            fibrin inadequateformation fibrin removal

                            Fibrin deposition

                            Inflammation

                            Coagulation

                            Stago Celebrates Lab Week 2017

                            NA

                            Stago 247 Educational Webinar Sites

                            wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                            wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                            Stago Educational Apps

                            HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                            iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                            BREAK

                            Diagnostic and Management Approach for DIC

                            Diagnosis of DIC

                            Clinical diagnosis is obvious in cases of overt DIC

                            Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                            Lab Diagnosis of DIC ndash Markers of Factor Consumption

                            Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                            Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                            Important to recognize simultaneous formation of thrombin and plasmin

                            Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                            Lab Diagnosis of DIC ndash Screening Tests

                            Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                            Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                            fibrinogen level) repeat testing assesses progression

                            Screening tests not clinically specific or sensitive for DIC

                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                            Laboratory Changes in Overt DIC

                            DIC Diagnostic Practices Over Time

                            Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                            British Journal of Haematology Overt DIC Score

                            Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                            ISTH Step by Step DIC Algorithm

                            Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                            US Based Validation of ISTH DIC Score

                            When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                            Differential Diagnosis in DIC

                            aHUS atypical hemolytic uremic syndrome

                            HUS hemolytic uremic syndrome

                            HIT heparin-induced thrombocytopenia

                            ITP immune thrombocytopenic purpura

                            TTP thrombotic thrombocytopenic purpura

                            DIC and MAHA

                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                            lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                            When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                            DIC Management Goals

                            Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                            Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                            DIC Management and Treatment

                            Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                            Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                            requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                            Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                            DIC Management Strategies

                            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                            Anticoagulant Factor Concentrate Treatment

                            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                            Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                            Anticoagulant Factor Concentrate Treatment Trials

                            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                            Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                            Markers of Thrombin amp Plasmin Generation in DIC

                            D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                            Cut-off value

                            Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                            degradation products Sensitive assay typically with cutoff adapted for DIC

                            D-dimer FDPs and DIC

                            D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                            Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                            Follow Up of DIC State of Disease

                            Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                            Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                            FMD-Dimer in DIC Major Differences

                            onset of thrombosis

                            days

                            Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                            FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                            D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                            of Abnormal Results in Patients with Confirmed and Suspected DIC

                            0

                            20

                            40

                            60

                            80

                            100

                            94 85 90N = 62

                            Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                            Positivity of Test Results ISTH Score and Disease State

                            Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                            Red bar positive for 2 points of DIC score

                            Pink bar positive for 1-2 points of DIC score

                            HT hematopoietic tumor

                            IF infection

                            SC solid cancer

                            Markers in Patients with or without DIC

                            Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                            HT hematopoietic tumorIF infectionSC solid cancer

                            Comparing an Automated FM vs Manual FSP Test

                            Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                            Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                            Automated (Mitsubishi) vs Automated (Stago)

                            In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                            Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                            Diagnostic Performance of FM and D-dimer in DIC

                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                            Diagnostic Performance of FM and D-dimer in DIC

                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                            In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                            Diagnostic Performance of FM and D-dimer in DIC

                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                            In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                            Diagnostic Performance of FM and D-dimer in DIC

                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                            In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                            Diagnostic Performance of FM and D-dimer in DIC

                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                            Diagnostic Performance of FM and D-dimer in DIC

                            Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                            No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                            Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                            Diagnostic Performance of FM and D-dimer in DIC

                            Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                            Non Overt DIC Overt DIC

                            AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                            Trends in Markers of DIC for Different Patients

                            Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                            Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                            Trends in Markers of DIC for Different Patients

                            Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                            FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                            28 day outcome survival

                            28 day outcome death

                            Determination of Cutoffs of FM and D-dimer in DIC

                            Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                            Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                            Determination of Cutoffs of FM and D-dimer in DIC

                            Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                            Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                            DIC Case Studies

                            Case Study 1 - Presentation

                            18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                            Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                            WBC count 77 KμL 423 ndash 907 x KμL

                            RBC count 17 MμL 137 ndash 175 x MμL

                            Hemoglobin 67 gdL 137 ndash 175 gdL

                            Hematocrit 195 401 ndash 510

                            MCV 95 fL 790 ndash 922 fL

                            MPV 12 fL 94 ndash 124 fL

                            Platelet count 9 KμL 161 ndash 347 KμL

                            Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                            Lymphocytes monocytes eosinophils basophils all below normal range

                            PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                            APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                            Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                            D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                            Case Study 1 ndash Microscopy

                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                            Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                            Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                            DIC due to TF release by APL blasts

                            Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                            Transfusions to replace factors along with platelets and RBCs during APL treatment

                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                            20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                            Case Study 2 ndash Presentation

                            TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                            PT 30 sec 113 ndash 146 sec

                            APTT 75 sec 25 ndash 34 sec

                            D-dimer 078 microgml FEU lt050 microgml FEU

                            Fibrinogen 92 mgdl 150-400 mgdl

                            pH 728 738 to 742

                            PaO2 570 mmHg 80-100 mmHg

                            WBC 33 times 103mm3 40-11 times 103mm3

                            ALT 111 IUL 0ndash34 IUL

                            AST 61 IUL 0ndash34 IUL

                            BUN 303 mgdL 08-13 mgdL

                            Case Study 2 ndash Lab Results

                            Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                            Case Study 2 ndash Diagnosis

                            60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                            Case Study 3 ndash Presentation

                            TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                            PT 228 sec 113 ndash 146 sec

                            APTT 45 sec 25 ndash 34 sec

                            D-dimer 080 microgml FEU lt050 microgmL FEU

                            Fibrinogen 82 mgdL 150-400 mgdL

                            FV Normal 70-120

                            FVII Normal 55-170

                            FVIII Normal 60-150

                            Protein C Normal 70-130

                            Hb 134 gdL 14-16 gdL

                            WBC 81 times 103mm3 40-11 times 103mm3

                            ALT 32 IUL 0ndash34 IUL

                            AST 28 IUL 0ndash34 IUL

                            BUN 09 mgdL 08-13 mgdL

                            Case Study 3 ndash Lab Results

                            Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                            Case Study 3 ndash Diagnosis and Therapy

                            Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                            Case Study 4 ndash Presentation

                            TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                            PT 28 sec 113 ndash 146 sec

                            APTT 71 sec 25 ndash 34 sec

                            D-dimer 31 microgmL FEU lt050 microgml FEU

                            Fibrinogen 92 mgdL 150-400 mgdl

                            FV Normal 70-120

                            FVII Normal 55-170

                            FVIII Normal 60-150

                            Protein C Normal 70-130

                            Hb 158 gdL 14-16 gdL

                            WBC 71 times 103mm3 40-11 times 103mm3

                            ALT 60 IUL 0ndash34 IUL

                            AST 47 IUL 0ndash34 IUL

                            BUN 38 mgdL 08-13 mgdL

                            Case Study 4 ndash Lab Results

                            Lyme disease with DICProvide antibiotics with supportive measures

                            Case Study 4 ndash Diagnosis

                            55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                            Case Study 5 ndash Presentation

                            Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                            Case Study 5 ndash Lab Results and Time Course

                            Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                            TEST RESULT REFERENCE RANGE

                            Platelet count 33 x 109L 150-450 x 109L

                            PT 215 sec 103 ndash 128 sec

                            APTT 44 sec 26 ndash 36 sec

                            D-dimer 20 microgmL FEU lt025 microgml FEU

                            Fibrinogen 34 mgdL 200-375 mgdl

                            FII FV FVIII Low Not reported (NR)

                            FVII FIX FX vWF Normal NR

                            Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                            DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                            dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                            (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                            (D) Illustration demonstrating repair

                            Case Study 5 ndash Diagnosis and Treatment

                            Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                            29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                            Case Study 6 ndash Presentation

                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                            Case Study 6 ndash Lab Results

                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                            TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                            PT 63 sec gt control 113 ndash 146 sec

                            INR 658 1 ndash 125

                            APTT 80 sec gt control 25 ndash 34 sec

                            D-dimer gt200 microgmL DDU 02 microgmL DDU

                            Urine exam Proteinuria and hematuria 150-400 mgdl

                            Albumin 28 gdL NR

                            Hb 58 gdL NR

                            LDH 1196 UL NR

                            SGPT 144 IU NR

                            SGOT 88 IU NR

                            Bilirubin 32 mgdL NR

                            DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                            day postop

                            Case Study 6 ndash Diagnosis and Treatment

                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                            HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                            Case Study 6 ndash Discussion

                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                            44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                            Case Study 7 ndash Presentation

                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                            On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                            Case Study 7 ndash Presentation

                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                            Case Study 7 ndash Lab Results vs Time

                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                            Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                            Case Study 7 ndash Diagnosis and Treatment

                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                            On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                            Case Study 7 ndash Diagnosis and Treatment

                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                            DIC Take Home Messages

                            Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                            Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                            DIC

                            Thank you Questions

                            • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                            • Learning Objectives
                            • Slide Number 3
                            • Slide Number 4
                            • Slide Number 5
                            • Slide Number 6
                            • Slide Number 7
                            • Slide Number 8
                            • Wound Sealing
                            • The Three Steps of Hemostasis
                            • Vessel Wall
                            • Slide Number 12
                            • Slide Number 13
                            • Platelet Structure UnactivatedActivated
                            • Primary Hemostasis
                            • Primary Hemostasis Assays
                            • Slide Number 17
                            • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                            • Slide Number 19
                            • Coagulation factors
                            • Coagulation Assay Mechanisms
                            • Slide Number 22
                            • Fibrin Formation
                            • Slide Number 24
                            • Fibrinolysis Overview
                            • Fibrinolysis Overview
                            • Slide Number 27
                            • Fibrinolysis Releases D-dimers
                            • Basic Pathophysiology of DIC
                            • Disseminated Intravascular Coagulation (DIC)
                            • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                            • Clinical Conditions Associated With DIC
                            • Frequency of DIC in Selected Disease States
                            • Underlying Diseases in DIC Patients
                            • Slide Number 36
                            • Slide Number 37
                            • Slide Number 38
                            • Slide Number 39
                            • Pathophysiology of DIC
                            • Pathogenesis of DIC in Sepsis
                            • Host Response in Severe Sepsis
                            • Organ Failure in Severe Sepsis
                            • Mechanism of DIC in Organ Failure
                            • Interaction of Inflammation and Coagulation in Sepsis
                            • Slide Number 47
                            • Diverse and Opposing Effects of Thrombin
                            • Coagulation and Fibrinolysis in DIC
                            • Mechanism of DIC
                            • Pathophysiology of DIC
                            • Pathophysiology of DIC - Mechanism
                            • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                            • Sub-Acute and Non-Overt DIC Clinical Findings
                            • Pathophysiology of Overt DIC
                            • Physiopathology of DIC ndash Overt DIC Findings
                            • Slide Number 57
                            • Slide Number 58
                            • Slide Number 59
                            • Slide Number 60
                            • Slide Number 61
                            • BREAK
                            • Diagnostic and Management Approach for DIC
                            • Diagnosis of DIC
                            • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                            • Lab Diagnosis of DIC ndash Screening Tests
                            • Slide Number 67
                            • Slide Number 68
                            • British Journal of Haematology Overt DIC Score
                            • Slide Number 70
                            • Slide Number 71
                            • Slide Number 72
                            • Slide Number 73
                            • DIC Management Goals
                            • DIC Management and Treatment
                            • DIC Management Strategies
                            • Anticoagulant Factor Concentrate Treatment
                            • Anticoagulant Factor Concentrate Treatment Trials
                            • Markers of Thrombin amp Plasmin Generation in DIC
                            • D-dimer FDPs and DIC
                            • D-Dimer and FDPs in DIC
                            • Follow Up of DIC State of Disease
                            • FMD-Dimer in DIC Major Differences
                            • of Abnormal Results in Patients with Confirmed and Suspected DIC
                            • Slide Number 85
                            • Slide Number 86
                            • Comparing an Automated FM vs Manual FSP Test
                            • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                            • Diagnostic Performance of FM and D-dimer in DIC
                            • Diagnostic Performance of FM and D-dimer in DIC
                            • Diagnostic Performance of FM and D-dimer in DIC
                            • Diagnostic Performance of FM and D-dimer in DIC
                            • Diagnostic Performance of FM and D-dimer in DIC
                            • Slide Number 94
                            • Slide Number 95
                            • Slide Number 96
                            • Slide Number 97
                            • Slide Number 98
                            • Slide Number 99
                            • DIC Case Studies
                            • Case Study 1 - Presentation
                            • Case Study 1 ndash Lab Results
                            • Case Study 1 ndash Microscopy
                            • Case Study 1 ndash Diagnosis and Therapy
                            • Slide Number 105
                            • Slide Number 106
                            • Slide Number 107
                            • Slide Number 108
                            • Slide Number 109
                            • Slide Number 110
                            • Slide Number 111
                            • Slide Number 112
                            • Slide Number 113
                            • Slide Number 114
                            • Slide Number 115
                            • Slide Number 116
                            • Slide Number 117
                            • Slide Number 118
                            • Slide Number 119
                            • Slide Number 120
                            • Slide Number 121
                            • Slide Number 122
                            • Slide Number 123
                            • Slide Number 124
                            • Slide Number 125
                            • DIC Take Home Messages
                            • Slide Number 127
                            • Slide Number 128

                              Primary Hemostasis

                              2) activation2nd shape changeamp release

                              platelet at rest 1) adhesion1st shape change

                              3) aggregation(not reversible)

                              Vasoconstriction occurs first

                              Platelets then aggregate on the break in the vessel wall

                              Primary Hemostasis AssaysRoutine Platelet count PT APTT TT

                              Follow-up von Willebrand Factor Antigen determination Activity Factor VIII PFA-100 Platelet aggregation studies

                              SpecializedSend Out Activation markers (b-TG PF4 GPV) Specialized tests for platelet function

                              Aim is to strengthen the platelet plug

                              Coagulation

                              Coagulation is a balancebetween pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis

                              THROMBIN

                              Fibrinogen Fibrin

                              bull Triggering agentsbull pro-enzyme enzyme (serine-protease FIIa FVIIa FIXa FXa)bull Cofactors (FVa amp FVIIIa)

                              bull Serine-protease inhibitor Antithrombin (AT) bull Cofactorsinhibitors Protein C Sbull Tissue factor pathway inhibitor (TFPI)

                              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                              Coagulation Cascade Schematic

                              Coagulation factors

                              Historic name

                              Fibrinogen

                              Prothrombin

                              Proaccelerin

                              Proconvertin

                              Anti-hemophilic factor A

                              Anti-hemophilic factor B

                              Stuart factor

                              Rosenthal factor

                              Hageman factor

                              Fibrin Stabilizing Factor

                              Factor

                              I

                              II

                              V

                              VII

                              VIII

                              IX

                              X

                              XI

                              XII

                              XIII

                              Function

                              Substrate

                              Pro-enzyme

                              Pro-cofactor

                              Pro-enzyme

                              Pro-cofactor

                              Pro-enzyme

                              Pro-enzyme

                              Pro-enzyme

                              Pro-enzyme

                              Pro-enzyme

                              Pro-enzyme = Zymogen activation Active Enzyme

                              Coagulation Assay Mechanisms

                              aPTT Based

                              PT Based

                              PT Based

                              Fibrin Under Microscope

                              Weisel JW Structure of fibrin impact on clot stability J Thromb Haemost 2007 5 Suppl 1 116-24

                              Low thrombin concentration

                              High thrombin concentration

                              Fibrin Formation

                              Soluble FibrinPolymer

                              ThrombinFibrinogen

                              FM+ fibrinopeptides A amp B

                              Stabilized Fibrin clot(not soluble)

                              ThrombinXIII XIIIa

                              (Digestion of Fibrin)

                              Fibrinolysis

                              Fibrinolysis Overview

                              Destroys fibrin fibers

                              Destroys the scab (dried wound)

                              Maintains vessel integrity

                              Fibrinolysis Overview

                              Fibrin =cement fibers

                              Plasmin

                              Plasmin digests fibrin

                              t-PA

                              Pro Urokinase

                              Urokinase

                              PAI-1PAI-1

                              Plasminogen Plasmin

                              1st Step

                              2nd Step

                              Fibrinolysis Cascade

                              t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin

                              Extrinsic pathway(endothelia l cells)

                              Intrinsic pathway(plasma)

                              Fibrin clot

                              D-dimerFibrin degradation products

                              Fibrin

                              TAFIa

                              APAntiplasmin(amp a2-MG)

                              PK Kallikrein

                              XII

                              Fibrinolysis Releases D-dimers

                              D-dimer presence fibrin has been formed and digested in patients body

                              Normal D-dimer level no thrombosis occurred in the patient

                              Basic Pathophysiology of DIC

                              Disseminated Intravascular Coagulation (DIC)

                              Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management

                              Clinical Manifestations of DICOrgan Ischemic Hemorrhagic

                              Skin Pupura Fulminans Petechiae

                              Gangrene Echymoses

                              Acral cyanosis Oozing

                              CNS Deliriumcoma Intracranial

                              Infarcts Bleeding

                              Renal OliguriaAzotemia Hematuria

                              Cortical Necrosis

                              Cardiovascular Myocardial dysfunction

                              Pulmonary DyspneaHypoxia Hemorrhagic lung

                              Infarct

                              Gastrointestinal Ulcers infarcts Massive hemorrhage

                              Endocrine Adrenal infarcts

                              Purpura Fulminans with DIC Due to Meningococcal Sepsis

                              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                              Clinical Conditions Associated With DIC

                              Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                              Frequency of DIC in Selected Disease States

                              Disease Frequency

                              Gram-negative sepsis 30-50

                              Severe trauma and systemic inflammation 50-70

                              Metastasized tumors 15

                              Abruptio placentaamniotic fluid embolism 50

                              Severe preeclampsia 7

                              Giant hemangioma 25

                              Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                              Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017

                              Underlying Diseases in DIC Patients

                              In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively

                              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                              Epidemiology of DIC

                              Impact of DIC Status on Mortality - 1

                              Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8

                              Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC

                              Impact of DIC Status on Mortality - 2

                              Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                              Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients

                              Impact of Age on Mortality in DIC Patients

                              Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                              Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)

                              Pathophysiology of DIC

                              Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                              Pathogenesis of DIC in Sepsis

                              Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15

                              Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC

                              Host Response in Severe Sepsis

                              Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral

                              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                              Organ Failure in Severe Sepsis

                              Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure

                              Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51

                              Mechanism of DIC in Organ Failure

                              Underlying condition(sepsis trauma)

                              Cytokines

                              TF-mediatedactivation of coagulation

                              Depression of inhibitory systems

                              Reducesfibrinolysis

                              Fibrin deposition

                              Organ failure

                              Inadequate fibrin removal

                              Fibrinformation

                              Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )

                              Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705

                              Interaction of Inflammation and Coagulation in Sepsis

                              Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines

                              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                              Mechanism of Multiple Organ Failure in DIC

                              Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

                              Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

                              lipopolysaccharides

                              cytokines

                              coagulation activation

                              mononuclear cell

                              tissue factor

                              Diverse and Opposing Effects of Thrombin

                              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                              Coagulation and Fibrinolysis in DIC

                              Soluble fibrin Polymer

                              XIIIa

                              D-Dimer

                              E

                              Fibrin clot

                              Fibrin Degradation Products

                              Fibrinogen Thrombin

                              Fibrinogen Degradation

                              Products

                              D E

                              Plasmin

                              DFM + fibrinopeptides

                              Soluble FM ComplexesPre-throm

                              boticPost-throm

                              botic

                              Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

                              Mechanism of DIC

                              THROMBOSIS

                              Fibrin

                              Blood activationEndothelial lysisTF expression

                              BLEEDING

                              FDPs

                              D-Dimer

                              Plasmin

                              Pathophysiology of DIC

                              1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

                              thromboplastin influx of activated cells (monocytes macrophages)

                              Results in an intravascular deposition of fibrin

                              Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

                              Second step Consumption and depletion of coagulation factors inhibitors (Protein C

                              Protein S AT) and platelets Local fibrinolytic response

                              bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

                              FDP and D-Dimer

                              Bleeding

                              Pathophysiology of DIC - Mechanism

                              Systemic activation of coagulation

                              Intravasculardepositionof fibrin

                              Thrombosis of small and midsize vessels

                              and organ failure

                              Depletion of platelets and

                              coagulation factors

                              Bleeding

                              Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                              Pathophysiology of DIC ndash 2 Types of Clinical pictures

                              Chronic = non - overt DICMay be unrecognized clinically

                              Acute = overt DIClife threatening bleedingor multiple organ failure

                              Sub-Acute and Non-Overt DIC Clinical Findings

                              Compensated non-overt DIC Steady low level or intermittent activation

                              bull Compensated by increased production of coagulation components and platelets

                              Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                              Risk of decompensation leading to overt DIC

                              Pathophysiology of Overt DIC

                              Massive activation of coagulation and fibrinolysis

                              Does not allow for compensatory efforts

                              Rapid depletion of coagulation factors inhibitors and platelets

                              Thrombosis multiple organ failures

                              Bleeding complications and shock

                              Physiopathology of DIC ndash Overt DIC Findings

                              Thrombin generation

                              Thrombosis

                              Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                              Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                              Plasmin generationHemorrhage

                              bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                              bull Tachycardia hypotension edema

                              Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                              Pathogenesis Pathways in DIC

                              Cytokines

                              TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                              fibrin inadequateformation fibrin removal

                              Fibrin deposition

                              Inflammation

                              Coagulation

                              Stago Celebrates Lab Week 2017

                              NA

                              Stago 247 Educational Webinar Sites

                              wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                              wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                              Stago Educational Apps

                              HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                              iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                              BREAK

                              Diagnostic and Management Approach for DIC

                              Diagnosis of DIC

                              Clinical diagnosis is obvious in cases of overt DIC

                              Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                              Lab Diagnosis of DIC ndash Markers of Factor Consumption

                              Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                              Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                              Important to recognize simultaneous formation of thrombin and plasmin

                              Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                              Lab Diagnosis of DIC ndash Screening Tests

                              Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                              Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                              fibrinogen level) repeat testing assesses progression

                              Screening tests not clinically specific or sensitive for DIC

                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                              Laboratory Changes in Overt DIC

                              DIC Diagnostic Practices Over Time

                              Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                              British Journal of Haematology Overt DIC Score

                              Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                              ISTH Step by Step DIC Algorithm

                              Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                              US Based Validation of ISTH DIC Score

                              When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                              Differential Diagnosis in DIC

                              aHUS atypical hemolytic uremic syndrome

                              HUS hemolytic uremic syndrome

                              HIT heparin-induced thrombocytopenia

                              ITP immune thrombocytopenic purpura

                              TTP thrombotic thrombocytopenic purpura

                              DIC and MAHA

                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                              lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                              When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                              DIC Management Goals

                              Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                              Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                              DIC Management and Treatment

                              Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                              Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                              requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                              Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                              DIC Management Strategies

                              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                              Anticoagulant Factor Concentrate Treatment

                              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                              Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                              Anticoagulant Factor Concentrate Treatment Trials

                              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                              Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                              Markers of Thrombin amp Plasmin Generation in DIC

                              D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                              Cut-off value

                              Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                              degradation products Sensitive assay typically with cutoff adapted for DIC

                              D-dimer FDPs and DIC

                              D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                              Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                              Follow Up of DIC State of Disease

                              Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                              Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                              FMD-Dimer in DIC Major Differences

                              onset of thrombosis

                              days

                              Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                              FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                              D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                              of Abnormal Results in Patients with Confirmed and Suspected DIC

                              0

                              20

                              40

                              60

                              80

                              100

                              94 85 90N = 62

                              Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                              Positivity of Test Results ISTH Score and Disease State

                              Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                              Red bar positive for 2 points of DIC score

                              Pink bar positive for 1-2 points of DIC score

                              HT hematopoietic tumor

                              IF infection

                              SC solid cancer

                              Markers in Patients with or without DIC

                              Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                              HT hematopoietic tumorIF infectionSC solid cancer

                              Comparing an Automated FM vs Manual FSP Test

                              Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                              Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                              Automated (Mitsubishi) vs Automated (Stago)

                              In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                              Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                              Diagnostic Performance of FM and D-dimer in DIC

                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                              Diagnostic Performance of FM and D-dimer in DIC

                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                              In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                              Diagnostic Performance of FM and D-dimer in DIC

                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                              In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                              Diagnostic Performance of FM and D-dimer in DIC

                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                              In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                              Diagnostic Performance of FM and D-dimer in DIC

                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                              Diagnostic Performance of FM and D-dimer in DIC

                              Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                              No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                              Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                              Diagnostic Performance of FM and D-dimer in DIC

                              Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                              Non Overt DIC Overt DIC

                              AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                              Trends in Markers of DIC for Different Patients

                              Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                              Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                              Trends in Markers of DIC for Different Patients

                              Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                              FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                              28 day outcome survival

                              28 day outcome death

                              Determination of Cutoffs of FM and D-dimer in DIC

                              Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                              Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                              Determination of Cutoffs of FM and D-dimer in DIC

                              Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                              Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                              DIC Case Studies

                              Case Study 1 - Presentation

                              18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                              Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                              WBC count 77 KμL 423 ndash 907 x KμL

                              RBC count 17 MμL 137 ndash 175 x MμL

                              Hemoglobin 67 gdL 137 ndash 175 gdL

                              Hematocrit 195 401 ndash 510

                              MCV 95 fL 790 ndash 922 fL

                              MPV 12 fL 94 ndash 124 fL

                              Platelet count 9 KμL 161 ndash 347 KμL

                              Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                              Lymphocytes monocytes eosinophils basophils all below normal range

                              PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                              APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                              Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                              D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                              Case Study 1 ndash Microscopy

                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                              Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                              Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                              DIC due to TF release by APL blasts

                              Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                              Transfusions to replace factors along with platelets and RBCs during APL treatment

                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                              20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                              Case Study 2 ndash Presentation

                              TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                              PT 30 sec 113 ndash 146 sec

                              APTT 75 sec 25 ndash 34 sec

                              D-dimer 078 microgml FEU lt050 microgml FEU

                              Fibrinogen 92 mgdl 150-400 mgdl

                              pH 728 738 to 742

                              PaO2 570 mmHg 80-100 mmHg

                              WBC 33 times 103mm3 40-11 times 103mm3

                              ALT 111 IUL 0ndash34 IUL

                              AST 61 IUL 0ndash34 IUL

                              BUN 303 mgdL 08-13 mgdL

                              Case Study 2 ndash Lab Results

                              Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                              Case Study 2 ndash Diagnosis

                              60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                              Case Study 3 ndash Presentation

                              TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                              PT 228 sec 113 ndash 146 sec

                              APTT 45 sec 25 ndash 34 sec

                              D-dimer 080 microgml FEU lt050 microgmL FEU

                              Fibrinogen 82 mgdL 150-400 mgdL

                              FV Normal 70-120

                              FVII Normal 55-170

                              FVIII Normal 60-150

                              Protein C Normal 70-130

                              Hb 134 gdL 14-16 gdL

                              WBC 81 times 103mm3 40-11 times 103mm3

                              ALT 32 IUL 0ndash34 IUL

                              AST 28 IUL 0ndash34 IUL

                              BUN 09 mgdL 08-13 mgdL

                              Case Study 3 ndash Lab Results

                              Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                              Case Study 3 ndash Diagnosis and Therapy

                              Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                              Case Study 4 ndash Presentation

                              TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                              PT 28 sec 113 ndash 146 sec

                              APTT 71 sec 25 ndash 34 sec

                              D-dimer 31 microgmL FEU lt050 microgml FEU

                              Fibrinogen 92 mgdL 150-400 mgdl

                              FV Normal 70-120

                              FVII Normal 55-170

                              FVIII Normal 60-150

                              Protein C Normal 70-130

                              Hb 158 gdL 14-16 gdL

                              WBC 71 times 103mm3 40-11 times 103mm3

                              ALT 60 IUL 0ndash34 IUL

                              AST 47 IUL 0ndash34 IUL

                              BUN 38 mgdL 08-13 mgdL

                              Case Study 4 ndash Lab Results

                              Lyme disease with DICProvide antibiotics with supportive measures

                              Case Study 4 ndash Diagnosis

                              55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                              Case Study 5 ndash Presentation

                              Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                              Case Study 5 ndash Lab Results and Time Course

                              Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                              TEST RESULT REFERENCE RANGE

                              Platelet count 33 x 109L 150-450 x 109L

                              PT 215 sec 103 ndash 128 sec

                              APTT 44 sec 26 ndash 36 sec

                              D-dimer 20 microgmL FEU lt025 microgml FEU

                              Fibrinogen 34 mgdL 200-375 mgdl

                              FII FV FVIII Low Not reported (NR)

                              FVII FIX FX vWF Normal NR

                              Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                              DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                              dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                              (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                              (D) Illustration demonstrating repair

                              Case Study 5 ndash Diagnosis and Treatment

                              Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                              29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                              Case Study 6 ndash Presentation

                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                              Case Study 6 ndash Lab Results

                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                              TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                              PT 63 sec gt control 113 ndash 146 sec

                              INR 658 1 ndash 125

                              APTT 80 sec gt control 25 ndash 34 sec

                              D-dimer gt200 microgmL DDU 02 microgmL DDU

                              Urine exam Proteinuria and hematuria 150-400 mgdl

                              Albumin 28 gdL NR

                              Hb 58 gdL NR

                              LDH 1196 UL NR

                              SGPT 144 IU NR

                              SGOT 88 IU NR

                              Bilirubin 32 mgdL NR

                              DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                              day postop

                              Case Study 6 ndash Diagnosis and Treatment

                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                              HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                              Case Study 6 ndash Discussion

                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                              44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                              Case Study 7 ndash Presentation

                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                              On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                              Case Study 7 ndash Presentation

                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                              Case Study 7 ndash Lab Results vs Time

                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                              Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                              Case Study 7 ndash Diagnosis and Treatment

                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                              On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                              Case Study 7 ndash Diagnosis and Treatment

                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                              DIC Take Home Messages

                              Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                              Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                              DIC

                              Thank you Questions

                              • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                              • Learning Objectives
                              • Slide Number 3
                              • Slide Number 4
                              • Slide Number 5
                              • Slide Number 6
                              • Slide Number 7
                              • Slide Number 8
                              • Wound Sealing
                              • The Three Steps of Hemostasis
                              • Vessel Wall
                              • Slide Number 12
                              • Slide Number 13
                              • Platelet Structure UnactivatedActivated
                              • Primary Hemostasis
                              • Primary Hemostasis Assays
                              • Slide Number 17
                              • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                              • Slide Number 19
                              • Coagulation factors
                              • Coagulation Assay Mechanisms
                              • Slide Number 22
                              • Fibrin Formation
                              • Slide Number 24
                              • Fibrinolysis Overview
                              • Fibrinolysis Overview
                              • Slide Number 27
                              • Fibrinolysis Releases D-dimers
                              • Basic Pathophysiology of DIC
                              • Disseminated Intravascular Coagulation (DIC)
                              • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                              • Clinical Conditions Associated With DIC
                              • Frequency of DIC in Selected Disease States
                              • Underlying Diseases in DIC Patients
                              • Slide Number 36
                              • Slide Number 37
                              • Slide Number 38
                              • Slide Number 39
                              • Pathophysiology of DIC
                              • Pathogenesis of DIC in Sepsis
                              • Host Response in Severe Sepsis
                              • Organ Failure in Severe Sepsis
                              • Mechanism of DIC in Organ Failure
                              • Interaction of Inflammation and Coagulation in Sepsis
                              • Slide Number 47
                              • Diverse and Opposing Effects of Thrombin
                              • Coagulation and Fibrinolysis in DIC
                              • Mechanism of DIC
                              • Pathophysiology of DIC
                              • Pathophysiology of DIC - Mechanism
                              • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                              • Sub-Acute and Non-Overt DIC Clinical Findings
                              • Pathophysiology of Overt DIC
                              • Physiopathology of DIC ndash Overt DIC Findings
                              • Slide Number 57
                              • Slide Number 58
                              • Slide Number 59
                              • Slide Number 60
                              • Slide Number 61
                              • BREAK
                              • Diagnostic and Management Approach for DIC
                              • Diagnosis of DIC
                              • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                              • Lab Diagnosis of DIC ndash Screening Tests
                              • Slide Number 67
                              • Slide Number 68
                              • British Journal of Haematology Overt DIC Score
                              • Slide Number 70
                              • Slide Number 71
                              • Slide Number 72
                              • Slide Number 73
                              • DIC Management Goals
                              • DIC Management and Treatment
                              • DIC Management Strategies
                              • Anticoagulant Factor Concentrate Treatment
                              • Anticoagulant Factor Concentrate Treatment Trials
                              • Markers of Thrombin amp Plasmin Generation in DIC
                              • D-dimer FDPs and DIC
                              • D-Dimer and FDPs in DIC
                              • Follow Up of DIC State of Disease
                              • FMD-Dimer in DIC Major Differences
                              • of Abnormal Results in Patients with Confirmed and Suspected DIC
                              • Slide Number 85
                              • Slide Number 86
                              • Comparing an Automated FM vs Manual FSP Test
                              • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                              • Diagnostic Performance of FM and D-dimer in DIC
                              • Diagnostic Performance of FM and D-dimer in DIC
                              • Diagnostic Performance of FM and D-dimer in DIC
                              • Diagnostic Performance of FM and D-dimer in DIC
                              • Diagnostic Performance of FM and D-dimer in DIC
                              • Slide Number 94
                              • Slide Number 95
                              • Slide Number 96
                              • Slide Number 97
                              • Slide Number 98
                              • Slide Number 99
                              • DIC Case Studies
                              • Case Study 1 - Presentation
                              • Case Study 1 ndash Lab Results
                              • Case Study 1 ndash Microscopy
                              • Case Study 1 ndash Diagnosis and Therapy
                              • Slide Number 105
                              • Slide Number 106
                              • Slide Number 107
                              • Slide Number 108
                              • Slide Number 109
                              • Slide Number 110
                              • Slide Number 111
                              • Slide Number 112
                              • Slide Number 113
                              • Slide Number 114
                              • Slide Number 115
                              • Slide Number 116
                              • Slide Number 117
                              • Slide Number 118
                              • Slide Number 119
                              • Slide Number 120
                              • Slide Number 121
                              • Slide Number 122
                              • Slide Number 123
                              • Slide Number 124
                              • Slide Number 125
                              • DIC Take Home Messages
                              • Slide Number 127
                              • Slide Number 128

                                Primary Hemostasis AssaysRoutine Platelet count PT APTT TT

                                Follow-up von Willebrand Factor Antigen determination Activity Factor VIII PFA-100 Platelet aggregation studies

                                SpecializedSend Out Activation markers (b-TG PF4 GPV) Specialized tests for platelet function

                                Aim is to strengthen the platelet plug

                                Coagulation

                                Coagulation is a balancebetween pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis

                                THROMBIN

                                Fibrinogen Fibrin

                                bull Triggering agentsbull pro-enzyme enzyme (serine-protease FIIa FVIIa FIXa FXa)bull Cofactors (FVa amp FVIIIa)

                                bull Serine-protease inhibitor Antithrombin (AT) bull Cofactorsinhibitors Protein C Sbull Tissue factor pathway inhibitor (TFPI)

                                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                Coagulation Cascade Schematic

                                Coagulation factors

                                Historic name

                                Fibrinogen

                                Prothrombin

                                Proaccelerin

                                Proconvertin

                                Anti-hemophilic factor A

                                Anti-hemophilic factor B

                                Stuart factor

                                Rosenthal factor

                                Hageman factor

                                Fibrin Stabilizing Factor

                                Factor

                                I

                                II

                                V

                                VII

                                VIII

                                IX

                                X

                                XI

                                XII

                                XIII

                                Function

                                Substrate

                                Pro-enzyme

                                Pro-cofactor

                                Pro-enzyme

                                Pro-cofactor

                                Pro-enzyme

                                Pro-enzyme

                                Pro-enzyme

                                Pro-enzyme

                                Pro-enzyme

                                Pro-enzyme = Zymogen activation Active Enzyme

                                Coagulation Assay Mechanisms

                                aPTT Based

                                PT Based

                                PT Based

                                Fibrin Under Microscope

                                Weisel JW Structure of fibrin impact on clot stability J Thromb Haemost 2007 5 Suppl 1 116-24

                                Low thrombin concentration

                                High thrombin concentration

                                Fibrin Formation

                                Soluble FibrinPolymer

                                ThrombinFibrinogen

                                FM+ fibrinopeptides A amp B

                                Stabilized Fibrin clot(not soluble)

                                ThrombinXIII XIIIa

                                (Digestion of Fibrin)

                                Fibrinolysis

                                Fibrinolysis Overview

                                Destroys fibrin fibers

                                Destroys the scab (dried wound)

                                Maintains vessel integrity

                                Fibrinolysis Overview

                                Fibrin =cement fibers

                                Plasmin

                                Plasmin digests fibrin

                                t-PA

                                Pro Urokinase

                                Urokinase

                                PAI-1PAI-1

                                Plasminogen Plasmin

                                1st Step

                                2nd Step

                                Fibrinolysis Cascade

                                t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin

                                Extrinsic pathway(endothelia l cells)

                                Intrinsic pathway(plasma)

                                Fibrin clot

                                D-dimerFibrin degradation products

                                Fibrin

                                TAFIa

                                APAntiplasmin(amp a2-MG)

                                PK Kallikrein

                                XII

                                Fibrinolysis Releases D-dimers

                                D-dimer presence fibrin has been formed and digested in patients body

                                Normal D-dimer level no thrombosis occurred in the patient

                                Basic Pathophysiology of DIC

                                Disseminated Intravascular Coagulation (DIC)

                                Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management

                                Clinical Manifestations of DICOrgan Ischemic Hemorrhagic

                                Skin Pupura Fulminans Petechiae

                                Gangrene Echymoses

                                Acral cyanosis Oozing

                                CNS Deliriumcoma Intracranial

                                Infarcts Bleeding

                                Renal OliguriaAzotemia Hematuria

                                Cortical Necrosis

                                Cardiovascular Myocardial dysfunction

                                Pulmonary DyspneaHypoxia Hemorrhagic lung

                                Infarct

                                Gastrointestinal Ulcers infarcts Massive hemorrhage

                                Endocrine Adrenal infarcts

                                Purpura Fulminans with DIC Due to Meningococcal Sepsis

                                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                Clinical Conditions Associated With DIC

                                Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                Frequency of DIC in Selected Disease States

                                Disease Frequency

                                Gram-negative sepsis 30-50

                                Severe trauma and systemic inflammation 50-70

                                Metastasized tumors 15

                                Abruptio placentaamniotic fluid embolism 50

                                Severe preeclampsia 7

                                Giant hemangioma 25

                                Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017

                                Underlying Diseases in DIC Patients

                                In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively

                                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                Epidemiology of DIC

                                Impact of DIC Status on Mortality - 1

                                Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8

                                Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC

                                Impact of DIC Status on Mortality - 2

                                Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients

                                Impact of Age on Mortality in DIC Patients

                                Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)

                                Pathophysiology of DIC

                                Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                Pathogenesis of DIC in Sepsis

                                Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15

                                Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC

                                Host Response in Severe Sepsis

                                Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral

                                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                Organ Failure in Severe Sepsis

                                Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure

                                Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51

                                Mechanism of DIC in Organ Failure

                                Underlying condition(sepsis trauma)

                                Cytokines

                                TF-mediatedactivation of coagulation

                                Depression of inhibitory systems

                                Reducesfibrinolysis

                                Fibrin deposition

                                Organ failure

                                Inadequate fibrin removal

                                Fibrinformation

                                Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )

                                Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705

                                Interaction of Inflammation and Coagulation in Sepsis

                                Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines

                                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                Mechanism of Multiple Organ Failure in DIC

                                Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

                                Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

                                lipopolysaccharides

                                cytokines

                                coagulation activation

                                mononuclear cell

                                tissue factor

                                Diverse and Opposing Effects of Thrombin

                                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                Coagulation and Fibrinolysis in DIC

                                Soluble fibrin Polymer

                                XIIIa

                                D-Dimer

                                E

                                Fibrin clot

                                Fibrin Degradation Products

                                Fibrinogen Thrombin

                                Fibrinogen Degradation

                                Products

                                D E

                                Plasmin

                                DFM + fibrinopeptides

                                Soluble FM ComplexesPre-throm

                                boticPost-throm

                                botic

                                Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

                                Mechanism of DIC

                                THROMBOSIS

                                Fibrin

                                Blood activationEndothelial lysisTF expression

                                BLEEDING

                                FDPs

                                D-Dimer

                                Plasmin

                                Pathophysiology of DIC

                                1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

                                thromboplastin influx of activated cells (monocytes macrophages)

                                Results in an intravascular deposition of fibrin

                                Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

                                Second step Consumption and depletion of coagulation factors inhibitors (Protein C

                                Protein S AT) and platelets Local fibrinolytic response

                                bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

                                FDP and D-Dimer

                                Bleeding

                                Pathophysiology of DIC - Mechanism

                                Systemic activation of coagulation

                                Intravasculardepositionof fibrin

                                Thrombosis of small and midsize vessels

                                and organ failure

                                Depletion of platelets and

                                coagulation factors

                                Bleeding

                                Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                Pathophysiology of DIC ndash 2 Types of Clinical pictures

                                Chronic = non - overt DICMay be unrecognized clinically

                                Acute = overt DIClife threatening bleedingor multiple organ failure

                                Sub-Acute and Non-Overt DIC Clinical Findings

                                Compensated non-overt DIC Steady low level or intermittent activation

                                bull Compensated by increased production of coagulation components and platelets

                                Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                                Risk of decompensation leading to overt DIC

                                Pathophysiology of Overt DIC

                                Massive activation of coagulation and fibrinolysis

                                Does not allow for compensatory efforts

                                Rapid depletion of coagulation factors inhibitors and platelets

                                Thrombosis multiple organ failures

                                Bleeding complications and shock

                                Physiopathology of DIC ndash Overt DIC Findings

                                Thrombin generation

                                Thrombosis

                                Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                                Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                                Plasmin generationHemorrhage

                                bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                                bull Tachycardia hypotension edema

                                Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                Pathogenesis Pathways in DIC

                                Cytokines

                                TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                                fibrin inadequateformation fibrin removal

                                Fibrin deposition

                                Inflammation

                                Coagulation

                                Stago Celebrates Lab Week 2017

                                NA

                                Stago 247 Educational Webinar Sites

                                wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                                wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                                Stago Educational Apps

                                HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                                iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                                BREAK

                                Diagnostic and Management Approach for DIC

                                Diagnosis of DIC

                                Clinical diagnosis is obvious in cases of overt DIC

                                Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                Important to recognize simultaneous formation of thrombin and plasmin

                                Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                Lab Diagnosis of DIC ndash Screening Tests

                                Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                fibrinogen level) repeat testing assesses progression

                                Screening tests not clinically specific or sensitive for DIC

                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                Laboratory Changes in Overt DIC

                                DIC Diagnostic Practices Over Time

                                Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                British Journal of Haematology Overt DIC Score

                                Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                ISTH Step by Step DIC Algorithm

                                Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                US Based Validation of ISTH DIC Score

                                When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                Differential Diagnosis in DIC

                                aHUS atypical hemolytic uremic syndrome

                                HUS hemolytic uremic syndrome

                                HIT heparin-induced thrombocytopenia

                                ITP immune thrombocytopenic purpura

                                TTP thrombotic thrombocytopenic purpura

                                DIC and MAHA

                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                DIC Management Goals

                                Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                DIC Management and Treatment

                                Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                DIC Management Strategies

                                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                Anticoagulant Factor Concentrate Treatment

                                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                Anticoagulant Factor Concentrate Treatment Trials

                                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                Markers of Thrombin amp Plasmin Generation in DIC

                                D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                Cut-off value

                                Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                degradation products Sensitive assay typically with cutoff adapted for DIC

                                D-dimer FDPs and DIC

                                D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                Follow Up of DIC State of Disease

                                Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                FMD-Dimer in DIC Major Differences

                                onset of thrombosis

                                days

                                Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                of Abnormal Results in Patients with Confirmed and Suspected DIC

                                0

                                20

                                40

                                60

                                80

                                100

                                94 85 90N = 62

                                Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                Positivity of Test Results ISTH Score and Disease State

                                Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                Red bar positive for 2 points of DIC score

                                Pink bar positive for 1-2 points of DIC score

                                HT hematopoietic tumor

                                IF infection

                                SC solid cancer

                                Markers in Patients with or without DIC

                                Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                HT hematopoietic tumorIF infectionSC solid cancer

                                Comparing an Automated FM vs Manual FSP Test

                                Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                Automated (Mitsubishi) vs Automated (Stago)

                                In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                Diagnostic Performance of FM and D-dimer in DIC

                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                Diagnostic Performance of FM and D-dimer in DIC

                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                Diagnostic Performance of FM and D-dimer in DIC

                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                Diagnostic Performance of FM and D-dimer in DIC

                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                Diagnostic Performance of FM and D-dimer in DIC

                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                Diagnostic Performance of FM and D-dimer in DIC

                                Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                Diagnostic Performance of FM and D-dimer in DIC

                                Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                Non Overt DIC Overt DIC

                                AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                Trends in Markers of DIC for Different Patients

                                Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                Trends in Markers of DIC for Different Patients

                                Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                28 day outcome survival

                                28 day outcome death

                                Determination of Cutoffs of FM and D-dimer in DIC

                                Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                Determination of Cutoffs of FM and D-dimer in DIC

                                Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                DIC Case Studies

                                Case Study 1 - Presentation

                                18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                WBC count 77 KμL 423 ndash 907 x KμL

                                RBC count 17 MμL 137 ndash 175 x MμL

                                Hemoglobin 67 gdL 137 ndash 175 gdL

                                Hematocrit 195 401 ndash 510

                                MCV 95 fL 790 ndash 922 fL

                                MPV 12 fL 94 ndash 124 fL

                                Platelet count 9 KμL 161 ndash 347 KμL

                                Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                Lymphocytes monocytes eosinophils basophils all below normal range

                                PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                Case Study 1 ndash Microscopy

                                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                DIC due to TF release by APL blasts

                                Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                Transfusions to replace factors along with platelets and RBCs during APL treatment

                                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                Case Study 2 ndash Presentation

                                TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                PT 30 sec 113 ndash 146 sec

                                APTT 75 sec 25 ndash 34 sec

                                D-dimer 078 microgml FEU lt050 microgml FEU

                                Fibrinogen 92 mgdl 150-400 mgdl

                                pH 728 738 to 742

                                PaO2 570 mmHg 80-100 mmHg

                                WBC 33 times 103mm3 40-11 times 103mm3

                                ALT 111 IUL 0ndash34 IUL

                                AST 61 IUL 0ndash34 IUL

                                BUN 303 mgdL 08-13 mgdL

                                Case Study 2 ndash Lab Results

                                Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                Case Study 2 ndash Diagnosis

                                60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                Case Study 3 ndash Presentation

                                TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                PT 228 sec 113 ndash 146 sec

                                APTT 45 sec 25 ndash 34 sec

                                D-dimer 080 microgml FEU lt050 microgmL FEU

                                Fibrinogen 82 mgdL 150-400 mgdL

                                FV Normal 70-120

                                FVII Normal 55-170

                                FVIII Normal 60-150

                                Protein C Normal 70-130

                                Hb 134 gdL 14-16 gdL

                                WBC 81 times 103mm3 40-11 times 103mm3

                                ALT 32 IUL 0ndash34 IUL

                                AST 28 IUL 0ndash34 IUL

                                BUN 09 mgdL 08-13 mgdL

                                Case Study 3 ndash Lab Results

                                Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                Case Study 3 ndash Diagnosis and Therapy

                                Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                Case Study 4 ndash Presentation

                                TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                PT 28 sec 113 ndash 146 sec

                                APTT 71 sec 25 ndash 34 sec

                                D-dimer 31 microgmL FEU lt050 microgml FEU

                                Fibrinogen 92 mgdL 150-400 mgdl

                                FV Normal 70-120

                                FVII Normal 55-170

                                FVIII Normal 60-150

                                Protein C Normal 70-130

                                Hb 158 gdL 14-16 gdL

                                WBC 71 times 103mm3 40-11 times 103mm3

                                ALT 60 IUL 0ndash34 IUL

                                AST 47 IUL 0ndash34 IUL

                                BUN 38 mgdL 08-13 mgdL

                                Case Study 4 ndash Lab Results

                                Lyme disease with DICProvide antibiotics with supportive measures

                                Case Study 4 ndash Diagnosis

                                55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                Case Study 5 ndash Presentation

                                Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                Case Study 5 ndash Lab Results and Time Course

                                Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                TEST RESULT REFERENCE RANGE

                                Platelet count 33 x 109L 150-450 x 109L

                                PT 215 sec 103 ndash 128 sec

                                APTT 44 sec 26 ndash 36 sec

                                D-dimer 20 microgmL FEU lt025 microgml FEU

                                Fibrinogen 34 mgdL 200-375 mgdl

                                FII FV FVIII Low Not reported (NR)

                                FVII FIX FX vWF Normal NR

                                Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                (D) Illustration demonstrating repair

                                Case Study 5 ndash Diagnosis and Treatment

                                Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                Case Study 6 ndash Presentation

                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                Case Study 6 ndash Lab Results

                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                PT 63 sec gt control 113 ndash 146 sec

                                INR 658 1 ndash 125

                                APTT 80 sec gt control 25 ndash 34 sec

                                D-dimer gt200 microgmL DDU 02 microgmL DDU

                                Urine exam Proteinuria and hematuria 150-400 mgdl

                                Albumin 28 gdL NR

                                Hb 58 gdL NR

                                LDH 1196 UL NR

                                SGPT 144 IU NR

                                SGOT 88 IU NR

                                Bilirubin 32 mgdL NR

                                DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                day postop

                                Case Study 6 ndash Diagnosis and Treatment

                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                Case Study 6 ndash Discussion

                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                Case Study 7 ndash Presentation

                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                Case Study 7 ndash Presentation

                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                Case Study 7 ndash Lab Results vs Time

                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                Case Study 7 ndash Diagnosis and Treatment

                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                Case Study 7 ndash Diagnosis and Treatment

                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                DIC Take Home Messages

                                Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                DIC

                                Thank you Questions

                                • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                • Learning Objectives
                                • Slide Number 3
                                • Slide Number 4
                                • Slide Number 5
                                • Slide Number 6
                                • Slide Number 7
                                • Slide Number 8
                                • Wound Sealing
                                • The Three Steps of Hemostasis
                                • Vessel Wall
                                • Slide Number 12
                                • Slide Number 13
                                • Platelet Structure UnactivatedActivated
                                • Primary Hemostasis
                                • Primary Hemostasis Assays
                                • Slide Number 17
                                • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                • Slide Number 19
                                • Coagulation factors
                                • Coagulation Assay Mechanisms
                                • Slide Number 22
                                • Fibrin Formation
                                • Slide Number 24
                                • Fibrinolysis Overview
                                • Fibrinolysis Overview
                                • Slide Number 27
                                • Fibrinolysis Releases D-dimers
                                • Basic Pathophysiology of DIC
                                • Disseminated Intravascular Coagulation (DIC)
                                • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                • Clinical Conditions Associated With DIC
                                • Frequency of DIC in Selected Disease States
                                • Underlying Diseases in DIC Patients
                                • Slide Number 36
                                • Slide Number 37
                                • Slide Number 38
                                • Slide Number 39
                                • Pathophysiology of DIC
                                • Pathogenesis of DIC in Sepsis
                                • Host Response in Severe Sepsis
                                • Organ Failure in Severe Sepsis
                                • Mechanism of DIC in Organ Failure
                                • Interaction of Inflammation and Coagulation in Sepsis
                                • Slide Number 47
                                • Diverse and Opposing Effects of Thrombin
                                • Coagulation and Fibrinolysis in DIC
                                • Mechanism of DIC
                                • Pathophysiology of DIC
                                • Pathophysiology of DIC - Mechanism
                                • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                • Sub-Acute and Non-Overt DIC Clinical Findings
                                • Pathophysiology of Overt DIC
                                • Physiopathology of DIC ndash Overt DIC Findings
                                • Slide Number 57
                                • Slide Number 58
                                • Slide Number 59
                                • Slide Number 60
                                • Slide Number 61
                                • BREAK
                                • Diagnostic and Management Approach for DIC
                                • Diagnosis of DIC
                                • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                • Lab Diagnosis of DIC ndash Screening Tests
                                • Slide Number 67
                                • Slide Number 68
                                • British Journal of Haematology Overt DIC Score
                                • Slide Number 70
                                • Slide Number 71
                                • Slide Number 72
                                • Slide Number 73
                                • DIC Management Goals
                                • DIC Management and Treatment
                                • DIC Management Strategies
                                • Anticoagulant Factor Concentrate Treatment
                                • Anticoagulant Factor Concentrate Treatment Trials
                                • Markers of Thrombin amp Plasmin Generation in DIC
                                • D-dimer FDPs and DIC
                                • D-Dimer and FDPs in DIC
                                • Follow Up of DIC State of Disease
                                • FMD-Dimer in DIC Major Differences
                                • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                • Slide Number 85
                                • Slide Number 86
                                • Comparing an Automated FM vs Manual FSP Test
                                • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                • Diagnostic Performance of FM and D-dimer in DIC
                                • Diagnostic Performance of FM and D-dimer in DIC
                                • Diagnostic Performance of FM and D-dimer in DIC
                                • Diagnostic Performance of FM and D-dimer in DIC
                                • Diagnostic Performance of FM and D-dimer in DIC
                                • Slide Number 94
                                • Slide Number 95
                                • Slide Number 96
                                • Slide Number 97
                                • Slide Number 98
                                • Slide Number 99
                                • DIC Case Studies
                                • Case Study 1 - Presentation
                                • Case Study 1 ndash Lab Results
                                • Case Study 1 ndash Microscopy
                                • Case Study 1 ndash Diagnosis and Therapy
                                • Slide Number 105
                                • Slide Number 106
                                • Slide Number 107
                                • Slide Number 108
                                • Slide Number 109
                                • Slide Number 110
                                • Slide Number 111
                                • Slide Number 112
                                • Slide Number 113
                                • Slide Number 114
                                • Slide Number 115
                                • Slide Number 116
                                • Slide Number 117
                                • Slide Number 118
                                • Slide Number 119
                                • Slide Number 120
                                • Slide Number 121
                                • Slide Number 122
                                • Slide Number 123
                                • Slide Number 124
                                • Slide Number 125
                                • DIC Take Home Messages
                                • Slide Number 127
                                • Slide Number 128

                                  Aim is to strengthen the platelet plug

                                  Coagulation

                                  Coagulation is a balancebetween pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis

                                  THROMBIN

                                  Fibrinogen Fibrin

                                  bull Triggering agentsbull pro-enzyme enzyme (serine-protease FIIa FVIIa FIXa FXa)bull Cofactors (FVa amp FVIIIa)

                                  bull Serine-protease inhibitor Antithrombin (AT) bull Cofactorsinhibitors Protein C Sbull Tissue factor pathway inhibitor (TFPI)

                                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                  Coagulation Cascade Schematic

                                  Coagulation factors

                                  Historic name

                                  Fibrinogen

                                  Prothrombin

                                  Proaccelerin

                                  Proconvertin

                                  Anti-hemophilic factor A

                                  Anti-hemophilic factor B

                                  Stuart factor

                                  Rosenthal factor

                                  Hageman factor

                                  Fibrin Stabilizing Factor

                                  Factor

                                  I

                                  II

                                  V

                                  VII

                                  VIII

                                  IX

                                  X

                                  XI

                                  XII

                                  XIII

                                  Function

                                  Substrate

                                  Pro-enzyme

                                  Pro-cofactor

                                  Pro-enzyme

                                  Pro-cofactor

                                  Pro-enzyme

                                  Pro-enzyme

                                  Pro-enzyme

                                  Pro-enzyme

                                  Pro-enzyme

                                  Pro-enzyme = Zymogen activation Active Enzyme

                                  Coagulation Assay Mechanisms

                                  aPTT Based

                                  PT Based

                                  PT Based

                                  Fibrin Under Microscope

                                  Weisel JW Structure of fibrin impact on clot stability J Thromb Haemost 2007 5 Suppl 1 116-24

                                  Low thrombin concentration

                                  High thrombin concentration

                                  Fibrin Formation

                                  Soluble FibrinPolymer

                                  ThrombinFibrinogen

                                  FM+ fibrinopeptides A amp B

                                  Stabilized Fibrin clot(not soluble)

                                  ThrombinXIII XIIIa

                                  (Digestion of Fibrin)

                                  Fibrinolysis

                                  Fibrinolysis Overview

                                  Destroys fibrin fibers

                                  Destroys the scab (dried wound)

                                  Maintains vessel integrity

                                  Fibrinolysis Overview

                                  Fibrin =cement fibers

                                  Plasmin

                                  Plasmin digests fibrin

                                  t-PA

                                  Pro Urokinase

                                  Urokinase

                                  PAI-1PAI-1

                                  Plasminogen Plasmin

                                  1st Step

                                  2nd Step

                                  Fibrinolysis Cascade

                                  t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin

                                  Extrinsic pathway(endothelia l cells)

                                  Intrinsic pathway(plasma)

                                  Fibrin clot

                                  D-dimerFibrin degradation products

                                  Fibrin

                                  TAFIa

                                  APAntiplasmin(amp a2-MG)

                                  PK Kallikrein

                                  XII

                                  Fibrinolysis Releases D-dimers

                                  D-dimer presence fibrin has been formed and digested in patients body

                                  Normal D-dimer level no thrombosis occurred in the patient

                                  Basic Pathophysiology of DIC

                                  Disseminated Intravascular Coagulation (DIC)

                                  Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management

                                  Clinical Manifestations of DICOrgan Ischemic Hemorrhagic

                                  Skin Pupura Fulminans Petechiae

                                  Gangrene Echymoses

                                  Acral cyanosis Oozing

                                  CNS Deliriumcoma Intracranial

                                  Infarcts Bleeding

                                  Renal OliguriaAzotemia Hematuria

                                  Cortical Necrosis

                                  Cardiovascular Myocardial dysfunction

                                  Pulmonary DyspneaHypoxia Hemorrhagic lung

                                  Infarct

                                  Gastrointestinal Ulcers infarcts Massive hemorrhage

                                  Endocrine Adrenal infarcts

                                  Purpura Fulminans with DIC Due to Meningococcal Sepsis

                                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                  Clinical Conditions Associated With DIC

                                  Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                  Frequency of DIC in Selected Disease States

                                  Disease Frequency

                                  Gram-negative sepsis 30-50

                                  Severe trauma and systemic inflammation 50-70

                                  Metastasized tumors 15

                                  Abruptio placentaamniotic fluid embolism 50

                                  Severe preeclampsia 7

                                  Giant hemangioma 25

                                  Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                  Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017

                                  Underlying Diseases in DIC Patients

                                  In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively

                                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                  Epidemiology of DIC

                                  Impact of DIC Status on Mortality - 1

                                  Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8

                                  Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC

                                  Impact of DIC Status on Mortality - 2

                                  Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                  Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients

                                  Impact of Age on Mortality in DIC Patients

                                  Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                  Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)

                                  Pathophysiology of DIC

                                  Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                  Pathogenesis of DIC in Sepsis

                                  Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15

                                  Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC

                                  Host Response in Severe Sepsis

                                  Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral

                                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                  Organ Failure in Severe Sepsis

                                  Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure

                                  Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51

                                  Mechanism of DIC in Organ Failure

                                  Underlying condition(sepsis trauma)

                                  Cytokines

                                  TF-mediatedactivation of coagulation

                                  Depression of inhibitory systems

                                  Reducesfibrinolysis

                                  Fibrin deposition

                                  Organ failure

                                  Inadequate fibrin removal

                                  Fibrinformation

                                  Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )

                                  Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705

                                  Interaction of Inflammation and Coagulation in Sepsis

                                  Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines

                                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                  Mechanism of Multiple Organ Failure in DIC

                                  Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

                                  Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

                                  lipopolysaccharides

                                  cytokines

                                  coagulation activation

                                  mononuclear cell

                                  tissue factor

                                  Diverse and Opposing Effects of Thrombin

                                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                  Coagulation and Fibrinolysis in DIC

                                  Soluble fibrin Polymer

                                  XIIIa

                                  D-Dimer

                                  E

                                  Fibrin clot

                                  Fibrin Degradation Products

                                  Fibrinogen Thrombin

                                  Fibrinogen Degradation

                                  Products

                                  D E

                                  Plasmin

                                  DFM + fibrinopeptides

                                  Soluble FM ComplexesPre-throm

                                  boticPost-throm

                                  botic

                                  Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

                                  Mechanism of DIC

                                  THROMBOSIS

                                  Fibrin

                                  Blood activationEndothelial lysisTF expression

                                  BLEEDING

                                  FDPs

                                  D-Dimer

                                  Plasmin

                                  Pathophysiology of DIC

                                  1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

                                  thromboplastin influx of activated cells (monocytes macrophages)

                                  Results in an intravascular deposition of fibrin

                                  Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

                                  Second step Consumption and depletion of coagulation factors inhibitors (Protein C

                                  Protein S AT) and platelets Local fibrinolytic response

                                  bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

                                  FDP and D-Dimer

                                  Bleeding

                                  Pathophysiology of DIC - Mechanism

                                  Systemic activation of coagulation

                                  Intravasculardepositionof fibrin

                                  Thrombosis of small and midsize vessels

                                  and organ failure

                                  Depletion of platelets and

                                  coagulation factors

                                  Bleeding

                                  Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                  Pathophysiology of DIC ndash 2 Types of Clinical pictures

                                  Chronic = non - overt DICMay be unrecognized clinically

                                  Acute = overt DIClife threatening bleedingor multiple organ failure

                                  Sub-Acute and Non-Overt DIC Clinical Findings

                                  Compensated non-overt DIC Steady low level or intermittent activation

                                  bull Compensated by increased production of coagulation components and platelets

                                  Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                                  Risk of decompensation leading to overt DIC

                                  Pathophysiology of Overt DIC

                                  Massive activation of coagulation and fibrinolysis

                                  Does not allow for compensatory efforts

                                  Rapid depletion of coagulation factors inhibitors and platelets

                                  Thrombosis multiple organ failures

                                  Bleeding complications and shock

                                  Physiopathology of DIC ndash Overt DIC Findings

                                  Thrombin generation

                                  Thrombosis

                                  Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                                  Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                                  Plasmin generationHemorrhage

                                  bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                                  bull Tachycardia hypotension edema

                                  Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                  Pathogenesis Pathways in DIC

                                  Cytokines

                                  TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                                  fibrin inadequateformation fibrin removal

                                  Fibrin deposition

                                  Inflammation

                                  Coagulation

                                  Stago Celebrates Lab Week 2017

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                                  Stago 247 Educational Webinar Sites

                                  wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                                  wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                                  Stago Educational Apps

                                  HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                                  iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                                  BREAK

                                  Diagnostic and Management Approach for DIC

                                  Diagnosis of DIC

                                  Clinical diagnosis is obvious in cases of overt DIC

                                  Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                  Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                  Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                  Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                  Important to recognize simultaneous formation of thrombin and plasmin

                                  Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                  Lab Diagnosis of DIC ndash Screening Tests

                                  Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                  Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                  fibrinogen level) repeat testing assesses progression

                                  Screening tests not clinically specific or sensitive for DIC

                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                  Laboratory Changes in Overt DIC

                                  DIC Diagnostic Practices Over Time

                                  Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                  British Journal of Haematology Overt DIC Score

                                  Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                  ISTH Step by Step DIC Algorithm

                                  Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                  US Based Validation of ISTH DIC Score

                                  When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                  Differential Diagnosis in DIC

                                  aHUS atypical hemolytic uremic syndrome

                                  HUS hemolytic uremic syndrome

                                  HIT heparin-induced thrombocytopenia

                                  ITP immune thrombocytopenic purpura

                                  TTP thrombotic thrombocytopenic purpura

                                  DIC and MAHA

                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                  lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                  When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                  DIC Management Goals

                                  Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                  Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                  DIC Management and Treatment

                                  Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                  Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                  requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                  Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                  DIC Management Strategies

                                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                  Anticoagulant Factor Concentrate Treatment

                                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                  Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                  Anticoagulant Factor Concentrate Treatment Trials

                                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                  Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                  Markers of Thrombin amp Plasmin Generation in DIC

                                  D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                  Cut-off value

                                  Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                  degradation products Sensitive assay typically with cutoff adapted for DIC

                                  D-dimer FDPs and DIC

                                  D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                  Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                  Follow Up of DIC State of Disease

                                  Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                  Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                  FMD-Dimer in DIC Major Differences

                                  onset of thrombosis

                                  days

                                  Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                  FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                  D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                  of Abnormal Results in Patients with Confirmed and Suspected DIC

                                  0

                                  20

                                  40

                                  60

                                  80

                                  100

                                  94 85 90N = 62

                                  Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                  Positivity of Test Results ISTH Score and Disease State

                                  Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                  Red bar positive for 2 points of DIC score

                                  Pink bar positive for 1-2 points of DIC score

                                  HT hematopoietic tumor

                                  IF infection

                                  SC solid cancer

                                  Markers in Patients with or without DIC

                                  Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                  HT hematopoietic tumorIF infectionSC solid cancer

                                  Comparing an Automated FM vs Manual FSP Test

                                  Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                  Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                  Automated (Mitsubishi) vs Automated (Stago)

                                  In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                  Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                  Diagnostic Performance of FM and D-dimer in DIC

                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                  Diagnostic Performance of FM and D-dimer in DIC

                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                  In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                  Diagnostic Performance of FM and D-dimer in DIC

                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                  In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                  Diagnostic Performance of FM and D-dimer in DIC

                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                  In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                  Diagnostic Performance of FM and D-dimer in DIC

                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                  Diagnostic Performance of FM and D-dimer in DIC

                                  Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                  No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                  Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                  Diagnostic Performance of FM and D-dimer in DIC

                                  Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                  Non Overt DIC Overt DIC

                                  AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                  Trends in Markers of DIC for Different Patients

                                  Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                  Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                  Trends in Markers of DIC for Different Patients

                                  Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                  FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                  28 day outcome survival

                                  28 day outcome death

                                  Determination of Cutoffs of FM and D-dimer in DIC

                                  Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                  Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                  Determination of Cutoffs of FM and D-dimer in DIC

                                  Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                  Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                  DIC Case Studies

                                  Case Study 1 - Presentation

                                  18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                  Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                  WBC count 77 KμL 423 ndash 907 x KμL

                                  RBC count 17 MμL 137 ndash 175 x MμL

                                  Hemoglobin 67 gdL 137 ndash 175 gdL

                                  Hematocrit 195 401 ndash 510

                                  MCV 95 fL 790 ndash 922 fL

                                  MPV 12 fL 94 ndash 124 fL

                                  Platelet count 9 KμL 161 ndash 347 KμL

                                  Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                  Lymphocytes monocytes eosinophils basophils all below normal range

                                  PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                  APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                  Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                  D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                  Case Study 1 ndash Microscopy

                                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                  Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                  Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                  DIC due to TF release by APL blasts

                                  Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                  Transfusions to replace factors along with platelets and RBCs during APL treatment

                                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                  20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                  Case Study 2 ndash Presentation

                                  TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                  PT 30 sec 113 ndash 146 sec

                                  APTT 75 sec 25 ndash 34 sec

                                  D-dimer 078 microgml FEU lt050 microgml FEU

                                  Fibrinogen 92 mgdl 150-400 mgdl

                                  pH 728 738 to 742

                                  PaO2 570 mmHg 80-100 mmHg

                                  WBC 33 times 103mm3 40-11 times 103mm3

                                  ALT 111 IUL 0ndash34 IUL

                                  AST 61 IUL 0ndash34 IUL

                                  BUN 303 mgdL 08-13 mgdL

                                  Case Study 2 ndash Lab Results

                                  Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                  Case Study 2 ndash Diagnosis

                                  60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                  Case Study 3 ndash Presentation

                                  TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                  PT 228 sec 113 ndash 146 sec

                                  APTT 45 sec 25 ndash 34 sec

                                  D-dimer 080 microgml FEU lt050 microgmL FEU

                                  Fibrinogen 82 mgdL 150-400 mgdL

                                  FV Normal 70-120

                                  FVII Normal 55-170

                                  FVIII Normal 60-150

                                  Protein C Normal 70-130

                                  Hb 134 gdL 14-16 gdL

                                  WBC 81 times 103mm3 40-11 times 103mm3

                                  ALT 32 IUL 0ndash34 IUL

                                  AST 28 IUL 0ndash34 IUL

                                  BUN 09 mgdL 08-13 mgdL

                                  Case Study 3 ndash Lab Results

                                  Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                  Case Study 3 ndash Diagnosis and Therapy

                                  Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                  Case Study 4 ndash Presentation

                                  TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                  PT 28 sec 113 ndash 146 sec

                                  APTT 71 sec 25 ndash 34 sec

                                  D-dimer 31 microgmL FEU lt050 microgml FEU

                                  Fibrinogen 92 mgdL 150-400 mgdl

                                  FV Normal 70-120

                                  FVII Normal 55-170

                                  FVIII Normal 60-150

                                  Protein C Normal 70-130

                                  Hb 158 gdL 14-16 gdL

                                  WBC 71 times 103mm3 40-11 times 103mm3

                                  ALT 60 IUL 0ndash34 IUL

                                  AST 47 IUL 0ndash34 IUL

                                  BUN 38 mgdL 08-13 mgdL

                                  Case Study 4 ndash Lab Results

                                  Lyme disease with DICProvide antibiotics with supportive measures

                                  Case Study 4 ndash Diagnosis

                                  55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                  Case Study 5 ndash Presentation

                                  Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                  Case Study 5 ndash Lab Results and Time Course

                                  Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                  TEST RESULT REFERENCE RANGE

                                  Platelet count 33 x 109L 150-450 x 109L

                                  PT 215 sec 103 ndash 128 sec

                                  APTT 44 sec 26 ndash 36 sec

                                  D-dimer 20 microgmL FEU lt025 microgml FEU

                                  Fibrinogen 34 mgdL 200-375 mgdl

                                  FII FV FVIII Low Not reported (NR)

                                  FVII FIX FX vWF Normal NR

                                  Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                  DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                  dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                  (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                  (D) Illustration demonstrating repair

                                  Case Study 5 ndash Diagnosis and Treatment

                                  Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                  29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                  Case Study 6 ndash Presentation

                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                  Case Study 6 ndash Lab Results

                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                  TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                  PT 63 sec gt control 113 ndash 146 sec

                                  INR 658 1 ndash 125

                                  APTT 80 sec gt control 25 ndash 34 sec

                                  D-dimer gt200 microgmL DDU 02 microgmL DDU

                                  Urine exam Proteinuria and hematuria 150-400 mgdl

                                  Albumin 28 gdL NR

                                  Hb 58 gdL NR

                                  LDH 1196 UL NR

                                  SGPT 144 IU NR

                                  SGOT 88 IU NR

                                  Bilirubin 32 mgdL NR

                                  DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                  day postop

                                  Case Study 6 ndash Diagnosis and Treatment

                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                  HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                  Case Study 6 ndash Discussion

                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                  44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                  Case Study 7 ndash Presentation

                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                  On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                  Case Study 7 ndash Presentation

                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                  Case Study 7 ndash Lab Results vs Time

                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                  Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                  Case Study 7 ndash Diagnosis and Treatment

                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                  On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                  Case Study 7 ndash Diagnosis and Treatment

                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                  DIC Take Home Messages

                                  Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                  Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                  DIC

                                  Thank you Questions

                                  • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                  • Learning Objectives
                                  • Slide Number 3
                                  • Slide Number 4
                                  • Slide Number 5
                                  • Slide Number 6
                                  • Slide Number 7
                                  • Slide Number 8
                                  • Wound Sealing
                                  • The Three Steps of Hemostasis
                                  • Vessel Wall
                                  • Slide Number 12
                                  • Slide Number 13
                                  • Platelet Structure UnactivatedActivated
                                  • Primary Hemostasis
                                  • Primary Hemostasis Assays
                                  • Slide Number 17
                                  • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                  • Slide Number 19
                                  • Coagulation factors
                                  • Coagulation Assay Mechanisms
                                  • Slide Number 22
                                  • Fibrin Formation
                                  • Slide Number 24
                                  • Fibrinolysis Overview
                                  • Fibrinolysis Overview
                                  • Slide Number 27
                                  • Fibrinolysis Releases D-dimers
                                  • Basic Pathophysiology of DIC
                                  • Disseminated Intravascular Coagulation (DIC)
                                  • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                  • Clinical Conditions Associated With DIC
                                  • Frequency of DIC in Selected Disease States
                                  • Underlying Diseases in DIC Patients
                                  • Slide Number 36
                                  • Slide Number 37
                                  • Slide Number 38
                                  • Slide Number 39
                                  • Pathophysiology of DIC
                                  • Pathogenesis of DIC in Sepsis
                                  • Host Response in Severe Sepsis
                                  • Organ Failure in Severe Sepsis
                                  • Mechanism of DIC in Organ Failure
                                  • Interaction of Inflammation and Coagulation in Sepsis
                                  • Slide Number 47
                                  • Diverse and Opposing Effects of Thrombin
                                  • Coagulation and Fibrinolysis in DIC
                                  • Mechanism of DIC
                                  • Pathophysiology of DIC
                                  • Pathophysiology of DIC - Mechanism
                                  • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                  • Sub-Acute and Non-Overt DIC Clinical Findings
                                  • Pathophysiology of Overt DIC
                                  • Physiopathology of DIC ndash Overt DIC Findings
                                  • Slide Number 57
                                  • Slide Number 58
                                  • Slide Number 59
                                  • Slide Number 60
                                  • Slide Number 61
                                  • BREAK
                                  • Diagnostic and Management Approach for DIC
                                  • Diagnosis of DIC
                                  • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                  • Lab Diagnosis of DIC ndash Screening Tests
                                  • Slide Number 67
                                  • Slide Number 68
                                  • British Journal of Haematology Overt DIC Score
                                  • Slide Number 70
                                  • Slide Number 71
                                  • Slide Number 72
                                  • Slide Number 73
                                  • DIC Management Goals
                                  • DIC Management and Treatment
                                  • DIC Management Strategies
                                  • Anticoagulant Factor Concentrate Treatment
                                  • Anticoagulant Factor Concentrate Treatment Trials
                                  • Markers of Thrombin amp Plasmin Generation in DIC
                                  • D-dimer FDPs and DIC
                                  • D-Dimer and FDPs in DIC
                                  • Follow Up of DIC State of Disease
                                  • FMD-Dimer in DIC Major Differences
                                  • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                  • Slide Number 85
                                  • Slide Number 86
                                  • Comparing an Automated FM vs Manual FSP Test
                                  • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                  • Diagnostic Performance of FM and D-dimer in DIC
                                  • Diagnostic Performance of FM and D-dimer in DIC
                                  • Diagnostic Performance of FM and D-dimer in DIC
                                  • Diagnostic Performance of FM and D-dimer in DIC
                                  • Diagnostic Performance of FM and D-dimer in DIC
                                  • Slide Number 94
                                  • Slide Number 95
                                  • Slide Number 96
                                  • Slide Number 97
                                  • Slide Number 98
                                  • Slide Number 99
                                  • DIC Case Studies
                                  • Case Study 1 - Presentation
                                  • Case Study 1 ndash Lab Results
                                  • Case Study 1 ndash Microscopy
                                  • Case Study 1 ndash Diagnosis and Therapy
                                  • Slide Number 105
                                  • Slide Number 106
                                  • Slide Number 107
                                  • Slide Number 108
                                  • Slide Number 109
                                  • Slide Number 110
                                  • Slide Number 111
                                  • Slide Number 112
                                  • Slide Number 113
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                                  • Slide Number 115
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                                  • Slide Number 120
                                  • Slide Number 121
                                  • Slide Number 122
                                  • Slide Number 123
                                  • Slide Number 124
                                  • Slide Number 125
                                  • DIC Take Home Messages
                                  • Slide Number 127
                                  • Slide Number 128

                                    Coagulation is a balancebetween pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis

                                    THROMBIN

                                    Fibrinogen Fibrin

                                    bull Triggering agentsbull pro-enzyme enzyme (serine-protease FIIa FVIIa FIXa FXa)bull Cofactors (FVa amp FVIIIa)

                                    bull Serine-protease inhibitor Antithrombin (AT) bull Cofactorsinhibitors Protein C Sbull Tissue factor pathway inhibitor (TFPI)

                                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                    Coagulation Cascade Schematic

                                    Coagulation factors

                                    Historic name

                                    Fibrinogen

                                    Prothrombin

                                    Proaccelerin

                                    Proconvertin

                                    Anti-hemophilic factor A

                                    Anti-hemophilic factor B

                                    Stuart factor

                                    Rosenthal factor

                                    Hageman factor

                                    Fibrin Stabilizing Factor

                                    Factor

                                    I

                                    II

                                    V

                                    VII

                                    VIII

                                    IX

                                    X

                                    XI

                                    XII

                                    XIII

                                    Function

                                    Substrate

                                    Pro-enzyme

                                    Pro-cofactor

                                    Pro-enzyme

                                    Pro-cofactor

                                    Pro-enzyme

                                    Pro-enzyme

                                    Pro-enzyme

                                    Pro-enzyme

                                    Pro-enzyme

                                    Pro-enzyme = Zymogen activation Active Enzyme

                                    Coagulation Assay Mechanisms

                                    aPTT Based

                                    PT Based

                                    PT Based

                                    Fibrin Under Microscope

                                    Weisel JW Structure of fibrin impact on clot stability J Thromb Haemost 2007 5 Suppl 1 116-24

                                    Low thrombin concentration

                                    High thrombin concentration

                                    Fibrin Formation

                                    Soluble FibrinPolymer

                                    ThrombinFibrinogen

                                    FM+ fibrinopeptides A amp B

                                    Stabilized Fibrin clot(not soluble)

                                    ThrombinXIII XIIIa

                                    (Digestion of Fibrin)

                                    Fibrinolysis

                                    Fibrinolysis Overview

                                    Destroys fibrin fibers

                                    Destroys the scab (dried wound)

                                    Maintains vessel integrity

                                    Fibrinolysis Overview

                                    Fibrin =cement fibers

                                    Plasmin

                                    Plasmin digests fibrin

                                    t-PA

                                    Pro Urokinase

                                    Urokinase

                                    PAI-1PAI-1

                                    Plasminogen Plasmin

                                    1st Step

                                    2nd Step

                                    Fibrinolysis Cascade

                                    t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin

                                    Extrinsic pathway(endothelia l cells)

                                    Intrinsic pathway(plasma)

                                    Fibrin clot

                                    D-dimerFibrin degradation products

                                    Fibrin

                                    TAFIa

                                    APAntiplasmin(amp a2-MG)

                                    PK Kallikrein

                                    XII

                                    Fibrinolysis Releases D-dimers

                                    D-dimer presence fibrin has been formed and digested in patients body

                                    Normal D-dimer level no thrombosis occurred in the patient

                                    Basic Pathophysiology of DIC

                                    Disseminated Intravascular Coagulation (DIC)

                                    Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management

                                    Clinical Manifestations of DICOrgan Ischemic Hemorrhagic

                                    Skin Pupura Fulminans Petechiae

                                    Gangrene Echymoses

                                    Acral cyanosis Oozing

                                    CNS Deliriumcoma Intracranial

                                    Infarcts Bleeding

                                    Renal OliguriaAzotemia Hematuria

                                    Cortical Necrosis

                                    Cardiovascular Myocardial dysfunction

                                    Pulmonary DyspneaHypoxia Hemorrhagic lung

                                    Infarct

                                    Gastrointestinal Ulcers infarcts Massive hemorrhage

                                    Endocrine Adrenal infarcts

                                    Purpura Fulminans with DIC Due to Meningococcal Sepsis

                                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                    Clinical Conditions Associated With DIC

                                    Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                    Frequency of DIC in Selected Disease States

                                    Disease Frequency

                                    Gram-negative sepsis 30-50

                                    Severe trauma and systemic inflammation 50-70

                                    Metastasized tumors 15

                                    Abruptio placentaamniotic fluid embolism 50

                                    Severe preeclampsia 7

                                    Giant hemangioma 25

                                    Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                    Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017

                                    Underlying Diseases in DIC Patients

                                    In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively

                                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                    Epidemiology of DIC

                                    Impact of DIC Status on Mortality - 1

                                    Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8

                                    Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC

                                    Impact of DIC Status on Mortality - 2

                                    Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                    Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients

                                    Impact of Age on Mortality in DIC Patients

                                    Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                    Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)

                                    Pathophysiology of DIC

                                    Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                    Pathogenesis of DIC in Sepsis

                                    Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15

                                    Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC

                                    Host Response in Severe Sepsis

                                    Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral

                                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                    Organ Failure in Severe Sepsis

                                    Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure

                                    Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51

                                    Mechanism of DIC in Organ Failure

                                    Underlying condition(sepsis trauma)

                                    Cytokines

                                    TF-mediatedactivation of coagulation

                                    Depression of inhibitory systems

                                    Reducesfibrinolysis

                                    Fibrin deposition

                                    Organ failure

                                    Inadequate fibrin removal

                                    Fibrinformation

                                    Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )

                                    Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705

                                    Interaction of Inflammation and Coagulation in Sepsis

                                    Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines

                                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                    Mechanism of Multiple Organ Failure in DIC

                                    Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

                                    Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

                                    lipopolysaccharides

                                    cytokines

                                    coagulation activation

                                    mononuclear cell

                                    tissue factor

                                    Diverse and Opposing Effects of Thrombin

                                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                    Coagulation and Fibrinolysis in DIC

                                    Soluble fibrin Polymer

                                    XIIIa

                                    D-Dimer

                                    E

                                    Fibrin clot

                                    Fibrin Degradation Products

                                    Fibrinogen Thrombin

                                    Fibrinogen Degradation

                                    Products

                                    D E

                                    Plasmin

                                    DFM + fibrinopeptides

                                    Soluble FM ComplexesPre-throm

                                    boticPost-throm

                                    botic

                                    Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

                                    Mechanism of DIC

                                    THROMBOSIS

                                    Fibrin

                                    Blood activationEndothelial lysisTF expression

                                    BLEEDING

                                    FDPs

                                    D-Dimer

                                    Plasmin

                                    Pathophysiology of DIC

                                    1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

                                    thromboplastin influx of activated cells (monocytes macrophages)

                                    Results in an intravascular deposition of fibrin

                                    Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

                                    Second step Consumption and depletion of coagulation factors inhibitors (Protein C

                                    Protein S AT) and platelets Local fibrinolytic response

                                    bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

                                    FDP and D-Dimer

                                    Bleeding

                                    Pathophysiology of DIC - Mechanism

                                    Systemic activation of coagulation

                                    Intravasculardepositionof fibrin

                                    Thrombosis of small and midsize vessels

                                    and organ failure

                                    Depletion of platelets and

                                    coagulation factors

                                    Bleeding

                                    Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                    Pathophysiology of DIC ndash 2 Types of Clinical pictures

                                    Chronic = non - overt DICMay be unrecognized clinically

                                    Acute = overt DIClife threatening bleedingor multiple organ failure

                                    Sub-Acute and Non-Overt DIC Clinical Findings

                                    Compensated non-overt DIC Steady low level or intermittent activation

                                    bull Compensated by increased production of coagulation components and platelets

                                    Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                                    Risk of decompensation leading to overt DIC

                                    Pathophysiology of Overt DIC

                                    Massive activation of coagulation and fibrinolysis

                                    Does not allow for compensatory efforts

                                    Rapid depletion of coagulation factors inhibitors and platelets

                                    Thrombosis multiple organ failures

                                    Bleeding complications and shock

                                    Physiopathology of DIC ndash Overt DIC Findings

                                    Thrombin generation

                                    Thrombosis

                                    Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                                    Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                                    Plasmin generationHemorrhage

                                    bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                                    bull Tachycardia hypotension edema

                                    Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                    Pathogenesis Pathways in DIC

                                    Cytokines

                                    TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                                    fibrin inadequateformation fibrin removal

                                    Fibrin deposition

                                    Inflammation

                                    Coagulation

                                    Stago Celebrates Lab Week 2017

                                    NA

                                    Stago 247 Educational Webinar Sites

                                    wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                                    wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                                    Stago Educational Apps

                                    HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                                    iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                                    BREAK

                                    Diagnostic and Management Approach for DIC

                                    Diagnosis of DIC

                                    Clinical diagnosis is obvious in cases of overt DIC

                                    Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                    Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                    Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                    Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                    Important to recognize simultaneous formation of thrombin and plasmin

                                    Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                    Lab Diagnosis of DIC ndash Screening Tests

                                    Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                    Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                    fibrinogen level) repeat testing assesses progression

                                    Screening tests not clinically specific or sensitive for DIC

                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                    Laboratory Changes in Overt DIC

                                    DIC Diagnostic Practices Over Time

                                    Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                    British Journal of Haematology Overt DIC Score

                                    Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                    ISTH Step by Step DIC Algorithm

                                    Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                    US Based Validation of ISTH DIC Score

                                    When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                    Differential Diagnosis in DIC

                                    aHUS atypical hemolytic uremic syndrome

                                    HUS hemolytic uremic syndrome

                                    HIT heparin-induced thrombocytopenia

                                    ITP immune thrombocytopenic purpura

                                    TTP thrombotic thrombocytopenic purpura

                                    DIC and MAHA

                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                    lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                    When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                    DIC Management Goals

                                    Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                    Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                    DIC Management and Treatment

                                    Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                    Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                    requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                    Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                    DIC Management Strategies

                                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                    Anticoagulant Factor Concentrate Treatment

                                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                    Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                    Anticoagulant Factor Concentrate Treatment Trials

                                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                    Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                    Markers of Thrombin amp Plasmin Generation in DIC

                                    D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                    Cut-off value

                                    Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                    degradation products Sensitive assay typically with cutoff adapted for DIC

                                    D-dimer FDPs and DIC

                                    D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                    Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                    Follow Up of DIC State of Disease

                                    Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                    Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                    FMD-Dimer in DIC Major Differences

                                    onset of thrombosis

                                    days

                                    Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                    FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                    D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                    of Abnormal Results in Patients with Confirmed and Suspected DIC

                                    0

                                    20

                                    40

                                    60

                                    80

                                    100

                                    94 85 90N = 62

                                    Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                    Positivity of Test Results ISTH Score and Disease State

                                    Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                    Red bar positive for 2 points of DIC score

                                    Pink bar positive for 1-2 points of DIC score

                                    HT hematopoietic tumor

                                    IF infection

                                    SC solid cancer

                                    Markers in Patients with or without DIC

                                    Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                    HT hematopoietic tumorIF infectionSC solid cancer

                                    Comparing an Automated FM vs Manual FSP Test

                                    Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                    Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                    Automated (Mitsubishi) vs Automated (Stago)

                                    In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                    Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                    Diagnostic Performance of FM and D-dimer in DIC

                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                    Diagnostic Performance of FM and D-dimer in DIC

                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                    In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                    Diagnostic Performance of FM and D-dimer in DIC

                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                    In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                    Diagnostic Performance of FM and D-dimer in DIC

                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                    In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                    Diagnostic Performance of FM and D-dimer in DIC

                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                    Diagnostic Performance of FM and D-dimer in DIC

                                    Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                    No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                    Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                    Diagnostic Performance of FM and D-dimer in DIC

                                    Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                    Non Overt DIC Overt DIC

                                    AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                    Trends in Markers of DIC for Different Patients

                                    Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                    Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                    Trends in Markers of DIC for Different Patients

                                    Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                    FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                    28 day outcome survival

                                    28 day outcome death

                                    Determination of Cutoffs of FM and D-dimer in DIC

                                    Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                    Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                    Determination of Cutoffs of FM and D-dimer in DIC

                                    Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                    Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                    DIC Case Studies

                                    Case Study 1 - Presentation

                                    18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                    Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                    WBC count 77 KμL 423 ndash 907 x KμL

                                    RBC count 17 MμL 137 ndash 175 x MμL

                                    Hemoglobin 67 gdL 137 ndash 175 gdL

                                    Hematocrit 195 401 ndash 510

                                    MCV 95 fL 790 ndash 922 fL

                                    MPV 12 fL 94 ndash 124 fL

                                    Platelet count 9 KμL 161 ndash 347 KμL

                                    Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                    Lymphocytes monocytes eosinophils basophils all below normal range

                                    PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                    APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                    Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                    D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                    Case Study 1 ndash Microscopy

                                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                    Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                    Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                    DIC due to TF release by APL blasts

                                    Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                    Transfusions to replace factors along with platelets and RBCs during APL treatment

                                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                    20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                    Case Study 2 ndash Presentation

                                    TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                    PT 30 sec 113 ndash 146 sec

                                    APTT 75 sec 25 ndash 34 sec

                                    D-dimer 078 microgml FEU lt050 microgml FEU

                                    Fibrinogen 92 mgdl 150-400 mgdl

                                    pH 728 738 to 742

                                    PaO2 570 mmHg 80-100 mmHg

                                    WBC 33 times 103mm3 40-11 times 103mm3

                                    ALT 111 IUL 0ndash34 IUL

                                    AST 61 IUL 0ndash34 IUL

                                    BUN 303 mgdL 08-13 mgdL

                                    Case Study 2 ndash Lab Results

                                    Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                    Case Study 2 ndash Diagnosis

                                    60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                    Case Study 3 ndash Presentation

                                    TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                    PT 228 sec 113 ndash 146 sec

                                    APTT 45 sec 25 ndash 34 sec

                                    D-dimer 080 microgml FEU lt050 microgmL FEU

                                    Fibrinogen 82 mgdL 150-400 mgdL

                                    FV Normal 70-120

                                    FVII Normal 55-170

                                    FVIII Normal 60-150

                                    Protein C Normal 70-130

                                    Hb 134 gdL 14-16 gdL

                                    WBC 81 times 103mm3 40-11 times 103mm3

                                    ALT 32 IUL 0ndash34 IUL

                                    AST 28 IUL 0ndash34 IUL

                                    BUN 09 mgdL 08-13 mgdL

                                    Case Study 3 ndash Lab Results

                                    Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                    Case Study 3 ndash Diagnosis and Therapy

                                    Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                    Case Study 4 ndash Presentation

                                    TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                    PT 28 sec 113 ndash 146 sec

                                    APTT 71 sec 25 ndash 34 sec

                                    D-dimer 31 microgmL FEU lt050 microgml FEU

                                    Fibrinogen 92 mgdL 150-400 mgdl

                                    FV Normal 70-120

                                    FVII Normal 55-170

                                    FVIII Normal 60-150

                                    Protein C Normal 70-130

                                    Hb 158 gdL 14-16 gdL

                                    WBC 71 times 103mm3 40-11 times 103mm3

                                    ALT 60 IUL 0ndash34 IUL

                                    AST 47 IUL 0ndash34 IUL

                                    BUN 38 mgdL 08-13 mgdL

                                    Case Study 4 ndash Lab Results

                                    Lyme disease with DICProvide antibiotics with supportive measures

                                    Case Study 4 ndash Diagnosis

                                    55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                    Case Study 5 ndash Presentation

                                    Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                    Case Study 5 ndash Lab Results and Time Course

                                    Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                    TEST RESULT REFERENCE RANGE

                                    Platelet count 33 x 109L 150-450 x 109L

                                    PT 215 sec 103 ndash 128 sec

                                    APTT 44 sec 26 ndash 36 sec

                                    D-dimer 20 microgmL FEU lt025 microgml FEU

                                    Fibrinogen 34 mgdL 200-375 mgdl

                                    FII FV FVIII Low Not reported (NR)

                                    FVII FIX FX vWF Normal NR

                                    Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                    DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                    dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                    (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                    (D) Illustration demonstrating repair

                                    Case Study 5 ndash Diagnosis and Treatment

                                    Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                    29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                    Case Study 6 ndash Presentation

                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                    Case Study 6 ndash Lab Results

                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                    TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                    PT 63 sec gt control 113 ndash 146 sec

                                    INR 658 1 ndash 125

                                    APTT 80 sec gt control 25 ndash 34 sec

                                    D-dimer gt200 microgmL DDU 02 microgmL DDU

                                    Urine exam Proteinuria and hematuria 150-400 mgdl

                                    Albumin 28 gdL NR

                                    Hb 58 gdL NR

                                    LDH 1196 UL NR

                                    SGPT 144 IU NR

                                    SGOT 88 IU NR

                                    Bilirubin 32 mgdL NR

                                    DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                    day postop

                                    Case Study 6 ndash Diagnosis and Treatment

                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                    HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                    Case Study 6 ndash Discussion

                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                    44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                    Case Study 7 ndash Presentation

                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                    On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                    Case Study 7 ndash Presentation

                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                    Case Study 7 ndash Lab Results vs Time

                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                    Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                    Case Study 7 ndash Diagnosis and Treatment

                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                    On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                    Case Study 7 ndash Diagnosis and Treatment

                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                    DIC Take Home Messages

                                    Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                    Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                    DIC

                                    Thank you Questions

                                    • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                    • Learning Objectives
                                    • Slide Number 3
                                    • Slide Number 4
                                    • Slide Number 5
                                    • Slide Number 6
                                    • Slide Number 7
                                    • Slide Number 8
                                    • Wound Sealing
                                    • The Three Steps of Hemostasis
                                    • Vessel Wall
                                    • Slide Number 12
                                    • Slide Number 13
                                    • Platelet Structure UnactivatedActivated
                                    • Primary Hemostasis
                                    • Primary Hemostasis Assays
                                    • Slide Number 17
                                    • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                    • Slide Number 19
                                    • Coagulation factors
                                    • Coagulation Assay Mechanisms
                                    • Slide Number 22
                                    • Fibrin Formation
                                    • Slide Number 24
                                    • Fibrinolysis Overview
                                    • Fibrinolysis Overview
                                    • Slide Number 27
                                    • Fibrinolysis Releases D-dimers
                                    • Basic Pathophysiology of DIC
                                    • Disseminated Intravascular Coagulation (DIC)
                                    • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                    • Clinical Conditions Associated With DIC
                                    • Frequency of DIC in Selected Disease States
                                    • Underlying Diseases in DIC Patients
                                    • Slide Number 36
                                    • Slide Number 37
                                    • Slide Number 38
                                    • Slide Number 39
                                    • Pathophysiology of DIC
                                    • Pathogenesis of DIC in Sepsis
                                    • Host Response in Severe Sepsis
                                    • Organ Failure in Severe Sepsis
                                    • Mechanism of DIC in Organ Failure
                                    • Interaction of Inflammation and Coagulation in Sepsis
                                    • Slide Number 47
                                    • Diverse and Opposing Effects of Thrombin
                                    • Coagulation and Fibrinolysis in DIC
                                    • Mechanism of DIC
                                    • Pathophysiology of DIC
                                    • Pathophysiology of DIC - Mechanism
                                    • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                    • Sub-Acute and Non-Overt DIC Clinical Findings
                                    • Pathophysiology of Overt DIC
                                    • Physiopathology of DIC ndash Overt DIC Findings
                                    • Slide Number 57
                                    • Slide Number 58
                                    • Slide Number 59
                                    • Slide Number 60
                                    • Slide Number 61
                                    • BREAK
                                    • Diagnostic and Management Approach for DIC
                                    • Diagnosis of DIC
                                    • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                    • Lab Diagnosis of DIC ndash Screening Tests
                                    • Slide Number 67
                                    • Slide Number 68
                                    • British Journal of Haematology Overt DIC Score
                                    • Slide Number 70
                                    • Slide Number 71
                                    • Slide Number 72
                                    • Slide Number 73
                                    • DIC Management Goals
                                    • DIC Management and Treatment
                                    • DIC Management Strategies
                                    • Anticoagulant Factor Concentrate Treatment
                                    • Anticoagulant Factor Concentrate Treatment Trials
                                    • Markers of Thrombin amp Plasmin Generation in DIC
                                    • D-dimer FDPs and DIC
                                    • D-Dimer and FDPs in DIC
                                    • Follow Up of DIC State of Disease
                                    • FMD-Dimer in DIC Major Differences
                                    • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                    • Slide Number 85
                                    • Slide Number 86
                                    • Comparing an Automated FM vs Manual FSP Test
                                    • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                    • Diagnostic Performance of FM and D-dimer in DIC
                                    • Diagnostic Performance of FM and D-dimer in DIC
                                    • Diagnostic Performance of FM and D-dimer in DIC
                                    • Diagnostic Performance of FM and D-dimer in DIC
                                    • Diagnostic Performance of FM and D-dimer in DIC
                                    • Slide Number 94
                                    • Slide Number 95
                                    • Slide Number 96
                                    • Slide Number 97
                                    • Slide Number 98
                                    • Slide Number 99
                                    • DIC Case Studies
                                    • Case Study 1 - Presentation
                                    • Case Study 1 ndash Lab Results
                                    • Case Study 1 ndash Microscopy
                                    • Case Study 1 ndash Diagnosis and Therapy
                                    • Slide Number 105
                                    • Slide Number 106
                                    • Slide Number 107
                                    • Slide Number 108
                                    • Slide Number 109
                                    • Slide Number 110
                                    • Slide Number 111
                                    • Slide Number 112
                                    • Slide Number 113
                                    • Slide Number 114
                                    • Slide Number 115
                                    • Slide Number 116
                                    • Slide Number 117
                                    • Slide Number 118
                                    • Slide Number 119
                                    • Slide Number 120
                                    • Slide Number 121
                                    • Slide Number 122
                                    • Slide Number 123
                                    • Slide Number 124
                                    • Slide Number 125
                                    • DIC Take Home Messages
                                    • Slide Number 127
                                    • Slide Number 128

                                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                      Coagulation Cascade Schematic

                                      Coagulation factors

                                      Historic name

                                      Fibrinogen

                                      Prothrombin

                                      Proaccelerin

                                      Proconvertin

                                      Anti-hemophilic factor A

                                      Anti-hemophilic factor B

                                      Stuart factor

                                      Rosenthal factor

                                      Hageman factor

                                      Fibrin Stabilizing Factor

                                      Factor

                                      I

                                      II

                                      V

                                      VII

                                      VIII

                                      IX

                                      X

                                      XI

                                      XII

                                      XIII

                                      Function

                                      Substrate

                                      Pro-enzyme

                                      Pro-cofactor

                                      Pro-enzyme

                                      Pro-cofactor

                                      Pro-enzyme

                                      Pro-enzyme

                                      Pro-enzyme

                                      Pro-enzyme

                                      Pro-enzyme

                                      Pro-enzyme = Zymogen activation Active Enzyme

                                      Coagulation Assay Mechanisms

                                      aPTT Based

                                      PT Based

                                      PT Based

                                      Fibrin Under Microscope

                                      Weisel JW Structure of fibrin impact on clot stability J Thromb Haemost 2007 5 Suppl 1 116-24

                                      Low thrombin concentration

                                      High thrombin concentration

                                      Fibrin Formation

                                      Soluble FibrinPolymer

                                      ThrombinFibrinogen

                                      FM+ fibrinopeptides A amp B

                                      Stabilized Fibrin clot(not soluble)

                                      ThrombinXIII XIIIa

                                      (Digestion of Fibrin)

                                      Fibrinolysis

                                      Fibrinolysis Overview

                                      Destroys fibrin fibers

                                      Destroys the scab (dried wound)

                                      Maintains vessel integrity

                                      Fibrinolysis Overview

                                      Fibrin =cement fibers

                                      Plasmin

                                      Plasmin digests fibrin

                                      t-PA

                                      Pro Urokinase

                                      Urokinase

                                      PAI-1PAI-1

                                      Plasminogen Plasmin

                                      1st Step

                                      2nd Step

                                      Fibrinolysis Cascade

                                      t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin

                                      Extrinsic pathway(endothelia l cells)

                                      Intrinsic pathway(plasma)

                                      Fibrin clot

                                      D-dimerFibrin degradation products

                                      Fibrin

                                      TAFIa

                                      APAntiplasmin(amp a2-MG)

                                      PK Kallikrein

                                      XII

                                      Fibrinolysis Releases D-dimers

                                      D-dimer presence fibrin has been formed and digested in patients body

                                      Normal D-dimer level no thrombosis occurred in the patient

                                      Basic Pathophysiology of DIC

                                      Disseminated Intravascular Coagulation (DIC)

                                      Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management

                                      Clinical Manifestations of DICOrgan Ischemic Hemorrhagic

                                      Skin Pupura Fulminans Petechiae

                                      Gangrene Echymoses

                                      Acral cyanosis Oozing

                                      CNS Deliriumcoma Intracranial

                                      Infarcts Bleeding

                                      Renal OliguriaAzotemia Hematuria

                                      Cortical Necrosis

                                      Cardiovascular Myocardial dysfunction

                                      Pulmonary DyspneaHypoxia Hemorrhagic lung

                                      Infarct

                                      Gastrointestinal Ulcers infarcts Massive hemorrhage

                                      Endocrine Adrenal infarcts

                                      Purpura Fulminans with DIC Due to Meningococcal Sepsis

                                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                      Clinical Conditions Associated With DIC

                                      Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                      Frequency of DIC in Selected Disease States

                                      Disease Frequency

                                      Gram-negative sepsis 30-50

                                      Severe trauma and systemic inflammation 50-70

                                      Metastasized tumors 15

                                      Abruptio placentaamniotic fluid embolism 50

                                      Severe preeclampsia 7

                                      Giant hemangioma 25

                                      Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                      Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017

                                      Underlying Diseases in DIC Patients

                                      In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively

                                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                      Epidemiology of DIC

                                      Impact of DIC Status on Mortality - 1

                                      Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8

                                      Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC

                                      Impact of DIC Status on Mortality - 2

                                      Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                      Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients

                                      Impact of Age on Mortality in DIC Patients

                                      Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                      Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)

                                      Pathophysiology of DIC

                                      Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                      Pathogenesis of DIC in Sepsis

                                      Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15

                                      Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC

                                      Host Response in Severe Sepsis

                                      Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral

                                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                      Organ Failure in Severe Sepsis

                                      Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure

                                      Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51

                                      Mechanism of DIC in Organ Failure

                                      Underlying condition(sepsis trauma)

                                      Cytokines

                                      TF-mediatedactivation of coagulation

                                      Depression of inhibitory systems

                                      Reducesfibrinolysis

                                      Fibrin deposition

                                      Organ failure

                                      Inadequate fibrin removal

                                      Fibrinformation

                                      Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )

                                      Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705

                                      Interaction of Inflammation and Coagulation in Sepsis

                                      Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines

                                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                      Mechanism of Multiple Organ Failure in DIC

                                      Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

                                      Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

                                      lipopolysaccharides

                                      cytokines

                                      coagulation activation

                                      mononuclear cell

                                      tissue factor

                                      Diverse and Opposing Effects of Thrombin

                                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                      Coagulation and Fibrinolysis in DIC

                                      Soluble fibrin Polymer

                                      XIIIa

                                      D-Dimer

                                      E

                                      Fibrin clot

                                      Fibrin Degradation Products

                                      Fibrinogen Thrombin

                                      Fibrinogen Degradation

                                      Products

                                      D E

                                      Plasmin

                                      DFM + fibrinopeptides

                                      Soluble FM ComplexesPre-throm

                                      boticPost-throm

                                      botic

                                      Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

                                      Mechanism of DIC

                                      THROMBOSIS

                                      Fibrin

                                      Blood activationEndothelial lysisTF expression

                                      BLEEDING

                                      FDPs

                                      D-Dimer

                                      Plasmin

                                      Pathophysiology of DIC

                                      1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

                                      thromboplastin influx of activated cells (monocytes macrophages)

                                      Results in an intravascular deposition of fibrin

                                      Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

                                      Second step Consumption and depletion of coagulation factors inhibitors (Protein C

                                      Protein S AT) and platelets Local fibrinolytic response

                                      bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

                                      FDP and D-Dimer

                                      Bleeding

                                      Pathophysiology of DIC - Mechanism

                                      Systemic activation of coagulation

                                      Intravasculardepositionof fibrin

                                      Thrombosis of small and midsize vessels

                                      and organ failure

                                      Depletion of platelets and

                                      coagulation factors

                                      Bleeding

                                      Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                      Pathophysiology of DIC ndash 2 Types of Clinical pictures

                                      Chronic = non - overt DICMay be unrecognized clinically

                                      Acute = overt DIClife threatening bleedingor multiple organ failure

                                      Sub-Acute and Non-Overt DIC Clinical Findings

                                      Compensated non-overt DIC Steady low level or intermittent activation

                                      bull Compensated by increased production of coagulation components and platelets

                                      Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                                      Risk of decompensation leading to overt DIC

                                      Pathophysiology of Overt DIC

                                      Massive activation of coagulation and fibrinolysis

                                      Does not allow for compensatory efforts

                                      Rapid depletion of coagulation factors inhibitors and platelets

                                      Thrombosis multiple organ failures

                                      Bleeding complications and shock

                                      Physiopathology of DIC ndash Overt DIC Findings

                                      Thrombin generation

                                      Thrombosis

                                      Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                                      Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                                      Plasmin generationHemorrhage

                                      bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                                      bull Tachycardia hypotension edema

                                      Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                      Pathogenesis Pathways in DIC

                                      Cytokines

                                      TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                                      fibrin inadequateformation fibrin removal

                                      Fibrin deposition

                                      Inflammation

                                      Coagulation

                                      Stago Celebrates Lab Week 2017

                                      NA

                                      Stago 247 Educational Webinar Sites

                                      wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                                      wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                                      Stago Educational Apps

                                      HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                                      iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                                      BREAK

                                      Diagnostic and Management Approach for DIC

                                      Diagnosis of DIC

                                      Clinical diagnosis is obvious in cases of overt DIC

                                      Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                      Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                      Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                      Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                      Important to recognize simultaneous formation of thrombin and plasmin

                                      Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                      Lab Diagnosis of DIC ndash Screening Tests

                                      Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                      Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                      fibrinogen level) repeat testing assesses progression

                                      Screening tests not clinically specific or sensitive for DIC

                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                      Laboratory Changes in Overt DIC

                                      DIC Diagnostic Practices Over Time

                                      Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                      British Journal of Haematology Overt DIC Score

                                      Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                      ISTH Step by Step DIC Algorithm

                                      Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                      US Based Validation of ISTH DIC Score

                                      When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                      Differential Diagnosis in DIC

                                      aHUS atypical hemolytic uremic syndrome

                                      HUS hemolytic uremic syndrome

                                      HIT heparin-induced thrombocytopenia

                                      ITP immune thrombocytopenic purpura

                                      TTP thrombotic thrombocytopenic purpura

                                      DIC and MAHA

                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                      lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                      When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                      DIC Management Goals

                                      Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                      Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                      DIC Management and Treatment

                                      Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                      Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                      requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                      Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                      DIC Management Strategies

                                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                      Anticoagulant Factor Concentrate Treatment

                                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                      Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                      Anticoagulant Factor Concentrate Treatment Trials

                                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                      Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                      Markers of Thrombin amp Plasmin Generation in DIC

                                      D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                      Cut-off value

                                      Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                      degradation products Sensitive assay typically with cutoff adapted for DIC

                                      D-dimer FDPs and DIC

                                      D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                      Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                      Follow Up of DIC State of Disease

                                      Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                      Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                      FMD-Dimer in DIC Major Differences

                                      onset of thrombosis

                                      days

                                      Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                      FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                      D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                      of Abnormal Results in Patients with Confirmed and Suspected DIC

                                      0

                                      20

                                      40

                                      60

                                      80

                                      100

                                      94 85 90N = 62

                                      Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                      Positivity of Test Results ISTH Score and Disease State

                                      Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                      Red bar positive for 2 points of DIC score

                                      Pink bar positive for 1-2 points of DIC score

                                      HT hematopoietic tumor

                                      IF infection

                                      SC solid cancer

                                      Markers in Patients with or without DIC

                                      Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                      HT hematopoietic tumorIF infectionSC solid cancer

                                      Comparing an Automated FM vs Manual FSP Test

                                      Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                      Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                      Automated (Mitsubishi) vs Automated (Stago)

                                      In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                      Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                      Diagnostic Performance of FM and D-dimer in DIC

                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                      Diagnostic Performance of FM and D-dimer in DIC

                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                      In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                      Diagnostic Performance of FM and D-dimer in DIC

                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                      In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                      Diagnostic Performance of FM and D-dimer in DIC

                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                      In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                      Diagnostic Performance of FM and D-dimer in DIC

                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                      Diagnostic Performance of FM and D-dimer in DIC

                                      Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                      No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                      Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                      Diagnostic Performance of FM and D-dimer in DIC

                                      Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                      Non Overt DIC Overt DIC

                                      AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                      Trends in Markers of DIC for Different Patients

                                      Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                      Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                      Trends in Markers of DIC for Different Patients

                                      Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                      FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                      28 day outcome survival

                                      28 day outcome death

                                      Determination of Cutoffs of FM and D-dimer in DIC

                                      Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                      Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                      Determination of Cutoffs of FM and D-dimer in DIC

                                      Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                      Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                      DIC Case Studies

                                      Case Study 1 - Presentation

                                      18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                      Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                      WBC count 77 KμL 423 ndash 907 x KμL

                                      RBC count 17 MμL 137 ndash 175 x MμL

                                      Hemoglobin 67 gdL 137 ndash 175 gdL

                                      Hematocrit 195 401 ndash 510

                                      MCV 95 fL 790 ndash 922 fL

                                      MPV 12 fL 94 ndash 124 fL

                                      Platelet count 9 KμL 161 ndash 347 KμL

                                      Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                      Lymphocytes monocytes eosinophils basophils all below normal range

                                      PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                      APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                      Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                      D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                      Case Study 1 ndash Microscopy

                                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                      Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                      Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                      DIC due to TF release by APL blasts

                                      Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                      Transfusions to replace factors along with platelets and RBCs during APL treatment

                                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                      20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                      Case Study 2 ndash Presentation

                                      TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                      PT 30 sec 113 ndash 146 sec

                                      APTT 75 sec 25 ndash 34 sec

                                      D-dimer 078 microgml FEU lt050 microgml FEU

                                      Fibrinogen 92 mgdl 150-400 mgdl

                                      pH 728 738 to 742

                                      PaO2 570 mmHg 80-100 mmHg

                                      WBC 33 times 103mm3 40-11 times 103mm3

                                      ALT 111 IUL 0ndash34 IUL

                                      AST 61 IUL 0ndash34 IUL

                                      BUN 303 mgdL 08-13 mgdL

                                      Case Study 2 ndash Lab Results

                                      Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                      Case Study 2 ndash Diagnosis

                                      60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                      Case Study 3 ndash Presentation

                                      TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                      PT 228 sec 113 ndash 146 sec

                                      APTT 45 sec 25 ndash 34 sec

                                      D-dimer 080 microgml FEU lt050 microgmL FEU

                                      Fibrinogen 82 mgdL 150-400 mgdL

                                      FV Normal 70-120

                                      FVII Normal 55-170

                                      FVIII Normal 60-150

                                      Protein C Normal 70-130

                                      Hb 134 gdL 14-16 gdL

                                      WBC 81 times 103mm3 40-11 times 103mm3

                                      ALT 32 IUL 0ndash34 IUL

                                      AST 28 IUL 0ndash34 IUL

                                      BUN 09 mgdL 08-13 mgdL

                                      Case Study 3 ndash Lab Results

                                      Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                      Case Study 3 ndash Diagnosis and Therapy

                                      Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                      Case Study 4 ndash Presentation

                                      TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                      PT 28 sec 113 ndash 146 sec

                                      APTT 71 sec 25 ndash 34 sec

                                      D-dimer 31 microgmL FEU lt050 microgml FEU

                                      Fibrinogen 92 mgdL 150-400 mgdl

                                      FV Normal 70-120

                                      FVII Normal 55-170

                                      FVIII Normal 60-150

                                      Protein C Normal 70-130

                                      Hb 158 gdL 14-16 gdL

                                      WBC 71 times 103mm3 40-11 times 103mm3

                                      ALT 60 IUL 0ndash34 IUL

                                      AST 47 IUL 0ndash34 IUL

                                      BUN 38 mgdL 08-13 mgdL

                                      Case Study 4 ndash Lab Results

                                      Lyme disease with DICProvide antibiotics with supportive measures

                                      Case Study 4 ndash Diagnosis

                                      55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                      Case Study 5 ndash Presentation

                                      Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                      Case Study 5 ndash Lab Results and Time Course

                                      Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                      TEST RESULT REFERENCE RANGE

                                      Platelet count 33 x 109L 150-450 x 109L

                                      PT 215 sec 103 ndash 128 sec

                                      APTT 44 sec 26 ndash 36 sec

                                      D-dimer 20 microgmL FEU lt025 microgml FEU

                                      Fibrinogen 34 mgdL 200-375 mgdl

                                      FII FV FVIII Low Not reported (NR)

                                      FVII FIX FX vWF Normal NR

                                      Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                      DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                      dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                      (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                      (D) Illustration demonstrating repair

                                      Case Study 5 ndash Diagnosis and Treatment

                                      Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                      29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                      Case Study 6 ndash Presentation

                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                      Case Study 6 ndash Lab Results

                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                      TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                      PT 63 sec gt control 113 ndash 146 sec

                                      INR 658 1 ndash 125

                                      APTT 80 sec gt control 25 ndash 34 sec

                                      D-dimer gt200 microgmL DDU 02 microgmL DDU

                                      Urine exam Proteinuria and hematuria 150-400 mgdl

                                      Albumin 28 gdL NR

                                      Hb 58 gdL NR

                                      LDH 1196 UL NR

                                      SGPT 144 IU NR

                                      SGOT 88 IU NR

                                      Bilirubin 32 mgdL NR

                                      DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                      day postop

                                      Case Study 6 ndash Diagnosis and Treatment

                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                      HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                      Case Study 6 ndash Discussion

                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                      44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                      Case Study 7 ndash Presentation

                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                      On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                      Case Study 7 ndash Presentation

                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                      Case Study 7 ndash Lab Results vs Time

                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                      Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                      Case Study 7 ndash Diagnosis and Treatment

                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                      On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                      Case Study 7 ndash Diagnosis and Treatment

                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                      DIC Take Home Messages

                                      Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                      Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                      DIC

                                      Thank you Questions

                                      • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                      • Learning Objectives
                                      • Slide Number 3
                                      • Slide Number 4
                                      • Slide Number 5
                                      • Slide Number 6
                                      • Slide Number 7
                                      • Slide Number 8
                                      • Wound Sealing
                                      • The Three Steps of Hemostasis
                                      • Vessel Wall
                                      • Slide Number 12
                                      • Slide Number 13
                                      • Platelet Structure UnactivatedActivated
                                      • Primary Hemostasis
                                      • Primary Hemostasis Assays
                                      • Slide Number 17
                                      • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                      • Slide Number 19
                                      • Coagulation factors
                                      • Coagulation Assay Mechanisms
                                      • Slide Number 22
                                      • Fibrin Formation
                                      • Slide Number 24
                                      • Fibrinolysis Overview
                                      • Fibrinolysis Overview
                                      • Slide Number 27
                                      • Fibrinolysis Releases D-dimers
                                      • Basic Pathophysiology of DIC
                                      • Disseminated Intravascular Coagulation (DIC)
                                      • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                      • Clinical Conditions Associated With DIC
                                      • Frequency of DIC in Selected Disease States
                                      • Underlying Diseases in DIC Patients
                                      • Slide Number 36
                                      • Slide Number 37
                                      • Slide Number 38
                                      • Slide Number 39
                                      • Pathophysiology of DIC
                                      • Pathogenesis of DIC in Sepsis
                                      • Host Response in Severe Sepsis
                                      • Organ Failure in Severe Sepsis
                                      • Mechanism of DIC in Organ Failure
                                      • Interaction of Inflammation and Coagulation in Sepsis
                                      • Slide Number 47
                                      • Diverse and Opposing Effects of Thrombin
                                      • Coagulation and Fibrinolysis in DIC
                                      • Mechanism of DIC
                                      • Pathophysiology of DIC
                                      • Pathophysiology of DIC - Mechanism
                                      • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                      • Sub-Acute and Non-Overt DIC Clinical Findings
                                      • Pathophysiology of Overt DIC
                                      • Physiopathology of DIC ndash Overt DIC Findings
                                      • Slide Number 57
                                      • Slide Number 58
                                      • Slide Number 59
                                      • Slide Number 60
                                      • Slide Number 61
                                      • BREAK
                                      • Diagnostic and Management Approach for DIC
                                      • Diagnosis of DIC
                                      • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                      • Lab Diagnosis of DIC ndash Screening Tests
                                      • Slide Number 67
                                      • Slide Number 68
                                      • British Journal of Haematology Overt DIC Score
                                      • Slide Number 70
                                      • Slide Number 71
                                      • Slide Number 72
                                      • Slide Number 73
                                      • DIC Management Goals
                                      • DIC Management and Treatment
                                      • DIC Management Strategies
                                      • Anticoagulant Factor Concentrate Treatment
                                      • Anticoagulant Factor Concentrate Treatment Trials
                                      • Markers of Thrombin amp Plasmin Generation in DIC
                                      • D-dimer FDPs and DIC
                                      • D-Dimer and FDPs in DIC
                                      • Follow Up of DIC State of Disease
                                      • FMD-Dimer in DIC Major Differences
                                      • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                      • Slide Number 85
                                      • Slide Number 86
                                      • Comparing an Automated FM vs Manual FSP Test
                                      • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                      • Diagnostic Performance of FM and D-dimer in DIC
                                      • Diagnostic Performance of FM and D-dimer in DIC
                                      • Diagnostic Performance of FM and D-dimer in DIC
                                      • Diagnostic Performance of FM and D-dimer in DIC
                                      • Diagnostic Performance of FM and D-dimer in DIC
                                      • Slide Number 94
                                      • Slide Number 95
                                      • Slide Number 96
                                      • Slide Number 97
                                      • Slide Number 98
                                      • Slide Number 99
                                      • DIC Case Studies
                                      • Case Study 1 - Presentation
                                      • Case Study 1 ndash Lab Results
                                      • Case Study 1 ndash Microscopy
                                      • Case Study 1 ndash Diagnosis and Therapy
                                      • Slide Number 105
                                      • Slide Number 106
                                      • Slide Number 107
                                      • Slide Number 108
                                      • Slide Number 109
                                      • Slide Number 110
                                      • Slide Number 111
                                      • Slide Number 112
                                      • Slide Number 113
                                      • Slide Number 114
                                      • Slide Number 115
                                      • Slide Number 116
                                      • Slide Number 117
                                      • Slide Number 118
                                      • Slide Number 119
                                      • Slide Number 120
                                      • Slide Number 121
                                      • Slide Number 122
                                      • Slide Number 123
                                      • Slide Number 124
                                      • Slide Number 125
                                      • DIC Take Home Messages
                                      • Slide Number 127
                                      • Slide Number 128

                                        Coagulation factors

                                        Historic name

                                        Fibrinogen

                                        Prothrombin

                                        Proaccelerin

                                        Proconvertin

                                        Anti-hemophilic factor A

                                        Anti-hemophilic factor B

                                        Stuart factor

                                        Rosenthal factor

                                        Hageman factor

                                        Fibrin Stabilizing Factor

                                        Factor

                                        I

                                        II

                                        V

                                        VII

                                        VIII

                                        IX

                                        X

                                        XI

                                        XII

                                        XIII

                                        Function

                                        Substrate

                                        Pro-enzyme

                                        Pro-cofactor

                                        Pro-enzyme

                                        Pro-cofactor

                                        Pro-enzyme

                                        Pro-enzyme

                                        Pro-enzyme

                                        Pro-enzyme

                                        Pro-enzyme

                                        Pro-enzyme = Zymogen activation Active Enzyme

                                        Coagulation Assay Mechanisms

                                        aPTT Based

                                        PT Based

                                        PT Based

                                        Fibrin Under Microscope

                                        Weisel JW Structure of fibrin impact on clot stability J Thromb Haemost 2007 5 Suppl 1 116-24

                                        Low thrombin concentration

                                        High thrombin concentration

                                        Fibrin Formation

                                        Soluble FibrinPolymer

                                        ThrombinFibrinogen

                                        FM+ fibrinopeptides A amp B

                                        Stabilized Fibrin clot(not soluble)

                                        ThrombinXIII XIIIa

                                        (Digestion of Fibrin)

                                        Fibrinolysis

                                        Fibrinolysis Overview

                                        Destroys fibrin fibers

                                        Destroys the scab (dried wound)

                                        Maintains vessel integrity

                                        Fibrinolysis Overview

                                        Fibrin =cement fibers

                                        Plasmin

                                        Plasmin digests fibrin

                                        t-PA

                                        Pro Urokinase

                                        Urokinase

                                        PAI-1PAI-1

                                        Plasminogen Plasmin

                                        1st Step

                                        2nd Step

                                        Fibrinolysis Cascade

                                        t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin

                                        Extrinsic pathway(endothelia l cells)

                                        Intrinsic pathway(plasma)

                                        Fibrin clot

                                        D-dimerFibrin degradation products

                                        Fibrin

                                        TAFIa

                                        APAntiplasmin(amp a2-MG)

                                        PK Kallikrein

                                        XII

                                        Fibrinolysis Releases D-dimers

                                        D-dimer presence fibrin has been formed and digested in patients body

                                        Normal D-dimer level no thrombosis occurred in the patient

                                        Basic Pathophysiology of DIC

                                        Disseminated Intravascular Coagulation (DIC)

                                        Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management

                                        Clinical Manifestations of DICOrgan Ischemic Hemorrhagic

                                        Skin Pupura Fulminans Petechiae

                                        Gangrene Echymoses

                                        Acral cyanosis Oozing

                                        CNS Deliriumcoma Intracranial

                                        Infarcts Bleeding

                                        Renal OliguriaAzotemia Hematuria

                                        Cortical Necrosis

                                        Cardiovascular Myocardial dysfunction

                                        Pulmonary DyspneaHypoxia Hemorrhagic lung

                                        Infarct

                                        Gastrointestinal Ulcers infarcts Massive hemorrhage

                                        Endocrine Adrenal infarcts

                                        Purpura Fulminans with DIC Due to Meningococcal Sepsis

                                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                        Clinical Conditions Associated With DIC

                                        Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                        Frequency of DIC in Selected Disease States

                                        Disease Frequency

                                        Gram-negative sepsis 30-50

                                        Severe trauma and systemic inflammation 50-70

                                        Metastasized tumors 15

                                        Abruptio placentaamniotic fluid embolism 50

                                        Severe preeclampsia 7

                                        Giant hemangioma 25

                                        Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                        Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017

                                        Underlying Diseases in DIC Patients

                                        In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively

                                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                        Epidemiology of DIC

                                        Impact of DIC Status on Mortality - 1

                                        Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8

                                        Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC

                                        Impact of DIC Status on Mortality - 2

                                        Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                        Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients

                                        Impact of Age on Mortality in DIC Patients

                                        Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                        Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)

                                        Pathophysiology of DIC

                                        Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                        Pathogenesis of DIC in Sepsis

                                        Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15

                                        Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC

                                        Host Response in Severe Sepsis

                                        Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral

                                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                        Organ Failure in Severe Sepsis

                                        Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure

                                        Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51

                                        Mechanism of DIC in Organ Failure

                                        Underlying condition(sepsis trauma)

                                        Cytokines

                                        TF-mediatedactivation of coagulation

                                        Depression of inhibitory systems

                                        Reducesfibrinolysis

                                        Fibrin deposition

                                        Organ failure

                                        Inadequate fibrin removal

                                        Fibrinformation

                                        Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )

                                        Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705

                                        Interaction of Inflammation and Coagulation in Sepsis

                                        Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines

                                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                        Mechanism of Multiple Organ Failure in DIC

                                        Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

                                        Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

                                        lipopolysaccharides

                                        cytokines

                                        coagulation activation

                                        mononuclear cell

                                        tissue factor

                                        Diverse and Opposing Effects of Thrombin

                                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                        Coagulation and Fibrinolysis in DIC

                                        Soluble fibrin Polymer

                                        XIIIa

                                        D-Dimer

                                        E

                                        Fibrin clot

                                        Fibrin Degradation Products

                                        Fibrinogen Thrombin

                                        Fibrinogen Degradation

                                        Products

                                        D E

                                        Plasmin

                                        DFM + fibrinopeptides

                                        Soluble FM ComplexesPre-throm

                                        boticPost-throm

                                        botic

                                        Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

                                        Mechanism of DIC

                                        THROMBOSIS

                                        Fibrin

                                        Blood activationEndothelial lysisTF expression

                                        BLEEDING

                                        FDPs

                                        D-Dimer

                                        Plasmin

                                        Pathophysiology of DIC

                                        1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

                                        thromboplastin influx of activated cells (monocytes macrophages)

                                        Results in an intravascular deposition of fibrin

                                        Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

                                        Second step Consumption and depletion of coagulation factors inhibitors (Protein C

                                        Protein S AT) and platelets Local fibrinolytic response

                                        bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

                                        FDP and D-Dimer

                                        Bleeding

                                        Pathophysiology of DIC - Mechanism

                                        Systemic activation of coagulation

                                        Intravasculardepositionof fibrin

                                        Thrombosis of small and midsize vessels

                                        and organ failure

                                        Depletion of platelets and

                                        coagulation factors

                                        Bleeding

                                        Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                        Pathophysiology of DIC ndash 2 Types of Clinical pictures

                                        Chronic = non - overt DICMay be unrecognized clinically

                                        Acute = overt DIClife threatening bleedingor multiple organ failure

                                        Sub-Acute and Non-Overt DIC Clinical Findings

                                        Compensated non-overt DIC Steady low level or intermittent activation

                                        bull Compensated by increased production of coagulation components and platelets

                                        Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                                        Risk of decompensation leading to overt DIC

                                        Pathophysiology of Overt DIC

                                        Massive activation of coagulation and fibrinolysis

                                        Does not allow for compensatory efforts

                                        Rapid depletion of coagulation factors inhibitors and platelets

                                        Thrombosis multiple organ failures

                                        Bleeding complications and shock

                                        Physiopathology of DIC ndash Overt DIC Findings

                                        Thrombin generation

                                        Thrombosis

                                        Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                                        Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                                        Plasmin generationHemorrhage

                                        bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                                        bull Tachycardia hypotension edema

                                        Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                        Pathogenesis Pathways in DIC

                                        Cytokines

                                        TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                                        fibrin inadequateformation fibrin removal

                                        Fibrin deposition

                                        Inflammation

                                        Coagulation

                                        Stago Celebrates Lab Week 2017

                                        NA

                                        Stago 247 Educational Webinar Sites

                                        wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                                        wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                                        Stago Educational Apps

                                        HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                                        iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                                        BREAK

                                        Diagnostic and Management Approach for DIC

                                        Diagnosis of DIC

                                        Clinical diagnosis is obvious in cases of overt DIC

                                        Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                        Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                        Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                        Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                        Important to recognize simultaneous formation of thrombin and plasmin

                                        Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                        Lab Diagnosis of DIC ndash Screening Tests

                                        Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                        Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                        fibrinogen level) repeat testing assesses progression

                                        Screening tests not clinically specific or sensitive for DIC

                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                        Laboratory Changes in Overt DIC

                                        DIC Diagnostic Practices Over Time

                                        Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                        British Journal of Haematology Overt DIC Score

                                        Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                        ISTH Step by Step DIC Algorithm

                                        Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                        US Based Validation of ISTH DIC Score

                                        When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                        Differential Diagnosis in DIC

                                        aHUS atypical hemolytic uremic syndrome

                                        HUS hemolytic uremic syndrome

                                        HIT heparin-induced thrombocytopenia

                                        ITP immune thrombocytopenic purpura

                                        TTP thrombotic thrombocytopenic purpura

                                        DIC and MAHA

                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                        lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                        When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                        DIC Management Goals

                                        Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                        Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                        DIC Management and Treatment

                                        Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                        Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                        requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                        Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                        DIC Management Strategies

                                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                        Anticoagulant Factor Concentrate Treatment

                                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                        Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                        Anticoagulant Factor Concentrate Treatment Trials

                                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                        Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                        Markers of Thrombin amp Plasmin Generation in DIC

                                        D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                        Cut-off value

                                        Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                        degradation products Sensitive assay typically with cutoff adapted for DIC

                                        D-dimer FDPs and DIC

                                        D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                        Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                        Follow Up of DIC State of Disease

                                        Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                        Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                        FMD-Dimer in DIC Major Differences

                                        onset of thrombosis

                                        days

                                        Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                        FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                        D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                        of Abnormal Results in Patients with Confirmed and Suspected DIC

                                        0

                                        20

                                        40

                                        60

                                        80

                                        100

                                        94 85 90N = 62

                                        Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                        Positivity of Test Results ISTH Score and Disease State

                                        Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                        Red bar positive for 2 points of DIC score

                                        Pink bar positive for 1-2 points of DIC score

                                        HT hematopoietic tumor

                                        IF infection

                                        SC solid cancer

                                        Markers in Patients with or without DIC

                                        Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                        HT hematopoietic tumorIF infectionSC solid cancer

                                        Comparing an Automated FM vs Manual FSP Test

                                        Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                        Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                        Automated (Mitsubishi) vs Automated (Stago)

                                        In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                        Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                        Diagnostic Performance of FM and D-dimer in DIC

                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                        Diagnostic Performance of FM and D-dimer in DIC

                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                        In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                        Diagnostic Performance of FM and D-dimer in DIC

                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                        In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                        Diagnostic Performance of FM and D-dimer in DIC

                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                        In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                        Diagnostic Performance of FM and D-dimer in DIC

                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                        Diagnostic Performance of FM and D-dimer in DIC

                                        Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                        No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                        Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                        Diagnostic Performance of FM and D-dimer in DIC

                                        Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                        Non Overt DIC Overt DIC

                                        AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                        Trends in Markers of DIC for Different Patients

                                        Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                        Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                        Trends in Markers of DIC for Different Patients

                                        Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                        FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                        28 day outcome survival

                                        28 day outcome death

                                        Determination of Cutoffs of FM and D-dimer in DIC

                                        Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                        Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                        Determination of Cutoffs of FM and D-dimer in DIC

                                        Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                        Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                        DIC Case Studies

                                        Case Study 1 - Presentation

                                        18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                        Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                        WBC count 77 KμL 423 ndash 907 x KμL

                                        RBC count 17 MμL 137 ndash 175 x MμL

                                        Hemoglobin 67 gdL 137 ndash 175 gdL

                                        Hematocrit 195 401 ndash 510

                                        MCV 95 fL 790 ndash 922 fL

                                        MPV 12 fL 94 ndash 124 fL

                                        Platelet count 9 KμL 161 ndash 347 KμL

                                        Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                        Lymphocytes monocytes eosinophils basophils all below normal range

                                        PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                        APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                        Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                        D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                        Case Study 1 ndash Microscopy

                                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                        Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                        Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                        DIC due to TF release by APL blasts

                                        Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                        Transfusions to replace factors along with platelets and RBCs during APL treatment

                                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                        20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                        Case Study 2 ndash Presentation

                                        TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                        PT 30 sec 113 ndash 146 sec

                                        APTT 75 sec 25 ndash 34 sec

                                        D-dimer 078 microgml FEU lt050 microgml FEU

                                        Fibrinogen 92 mgdl 150-400 mgdl

                                        pH 728 738 to 742

                                        PaO2 570 mmHg 80-100 mmHg

                                        WBC 33 times 103mm3 40-11 times 103mm3

                                        ALT 111 IUL 0ndash34 IUL

                                        AST 61 IUL 0ndash34 IUL

                                        BUN 303 mgdL 08-13 mgdL

                                        Case Study 2 ndash Lab Results

                                        Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                        Case Study 2 ndash Diagnosis

                                        60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                        Case Study 3 ndash Presentation

                                        TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                        PT 228 sec 113 ndash 146 sec

                                        APTT 45 sec 25 ndash 34 sec

                                        D-dimer 080 microgml FEU lt050 microgmL FEU

                                        Fibrinogen 82 mgdL 150-400 mgdL

                                        FV Normal 70-120

                                        FVII Normal 55-170

                                        FVIII Normal 60-150

                                        Protein C Normal 70-130

                                        Hb 134 gdL 14-16 gdL

                                        WBC 81 times 103mm3 40-11 times 103mm3

                                        ALT 32 IUL 0ndash34 IUL

                                        AST 28 IUL 0ndash34 IUL

                                        BUN 09 mgdL 08-13 mgdL

                                        Case Study 3 ndash Lab Results

                                        Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                        Case Study 3 ndash Diagnosis and Therapy

                                        Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                        Case Study 4 ndash Presentation

                                        TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                        PT 28 sec 113 ndash 146 sec

                                        APTT 71 sec 25 ndash 34 sec

                                        D-dimer 31 microgmL FEU lt050 microgml FEU

                                        Fibrinogen 92 mgdL 150-400 mgdl

                                        FV Normal 70-120

                                        FVII Normal 55-170

                                        FVIII Normal 60-150

                                        Protein C Normal 70-130

                                        Hb 158 gdL 14-16 gdL

                                        WBC 71 times 103mm3 40-11 times 103mm3

                                        ALT 60 IUL 0ndash34 IUL

                                        AST 47 IUL 0ndash34 IUL

                                        BUN 38 mgdL 08-13 mgdL

                                        Case Study 4 ndash Lab Results

                                        Lyme disease with DICProvide antibiotics with supportive measures

                                        Case Study 4 ndash Diagnosis

                                        55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                        Case Study 5 ndash Presentation

                                        Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                        Case Study 5 ndash Lab Results and Time Course

                                        Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                        TEST RESULT REFERENCE RANGE

                                        Platelet count 33 x 109L 150-450 x 109L

                                        PT 215 sec 103 ndash 128 sec

                                        APTT 44 sec 26 ndash 36 sec

                                        D-dimer 20 microgmL FEU lt025 microgml FEU

                                        Fibrinogen 34 mgdL 200-375 mgdl

                                        FII FV FVIII Low Not reported (NR)

                                        FVII FIX FX vWF Normal NR

                                        Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                        DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                        dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                        (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                        (D) Illustration demonstrating repair

                                        Case Study 5 ndash Diagnosis and Treatment

                                        Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                        29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                        Case Study 6 ndash Presentation

                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                        Case Study 6 ndash Lab Results

                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                        TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                        PT 63 sec gt control 113 ndash 146 sec

                                        INR 658 1 ndash 125

                                        APTT 80 sec gt control 25 ndash 34 sec

                                        D-dimer gt200 microgmL DDU 02 microgmL DDU

                                        Urine exam Proteinuria and hematuria 150-400 mgdl

                                        Albumin 28 gdL NR

                                        Hb 58 gdL NR

                                        LDH 1196 UL NR

                                        SGPT 144 IU NR

                                        SGOT 88 IU NR

                                        Bilirubin 32 mgdL NR

                                        DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                        day postop

                                        Case Study 6 ndash Diagnosis and Treatment

                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                        HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                        Case Study 6 ndash Discussion

                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                        44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                        Case Study 7 ndash Presentation

                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                        On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                        Case Study 7 ndash Presentation

                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                        Case Study 7 ndash Lab Results vs Time

                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                        Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                        Case Study 7 ndash Diagnosis and Treatment

                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                        On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                        Case Study 7 ndash Diagnosis and Treatment

                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                        DIC Take Home Messages

                                        Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                        Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                        DIC

                                        Thank you Questions

                                        • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                        • Learning Objectives
                                        • Slide Number 3
                                        • Slide Number 4
                                        • Slide Number 5
                                        • Slide Number 6
                                        • Slide Number 7
                                        • Slide Number 8
                                        • Wound Sealing
                                        • The Three Steps of Hemostasis
                                        • Vessel Wall
                                        • Slide Number 12
                                        • Slide Number 13
                                        • Platelet Structure UnactivatedActivated
                                        • Primary Hemostasis
                                        • Primary Hemostasis Assays
                                        • Slide Number 17
                                        • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                        • Slide Number 19
                                        • Coagulation factors
                                        • Coagulation Assay Mechanisms
                                        • Slide Number 22
                                        • Fibrin Formation
                                        • Slide Number 24
                                        • Fibrinolysis Overview
                                        • Fibrinolysis Overview
                                        • Slide Number 27
                                        • Fibrinolysis Releases D-dimers
                                        • Basic Pathophysiology of DIC
                                        • Disseminated Intravascular Coagulation (DIC)
                                        • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                        • Clinical Conditions Associated With DIC
                                        • Frequency of DIC in Selected Disease States
                                        • Underlying Diseases in DIC Patients
                                        • Slide Number 36
                                        • Slide Number 37
                                        • Slide Number 38
                                        • Slide Number 39
                                        • Pathophysiology of DIC
                                        • Pathogenesis of DIC in Sepsis
                                        • Host Response in Severe Sepsis
                                        • Organ Failure in Severe Sepsis
                                        • Mechanism of DIC in Organ Failure
                                        • Interaction of Inflammation and Coagulation in Sepsis
                                        • Slide Number 47
                                        • Diverse and Opposing Effects of Thrombin
                                        • Coagulation and Fibrinolysis in DIC
                                        • Mechanism of DIC
                                        • Pathophysiology of DIC
                                        • Pathophysiology of DIC - Mechanism
                                        • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                        • Sub-Acute and Non-Overt DIC Clinical Findings
                                        • Pathophysiology of Overt DIC
                                        • Physiopathology of DIC ndash Overt DIC Findings
                                        • Slide Number 57
                                        • Slide Number 58
                                        • Slide Number 59
                                        • Slide Number 60
                                        • Slide Number 61
                                        • BREAK
                                        • Diagnostic and Management Approach for DIC
                                        • Diagnosis of DIC
                                        • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                        • Lab Diagnosis of DIC ndash Screening Tests
                                        • Slide Number 67
                                        • Slide Number 68
                                        • British Journal of Haematology Overt DIC Score
                                        • Slide Number 70
                                        • Slide Number 71
                                        • Slide Number 72
                                        • Slide Number 73
                                        • DIC Management Goals
                                        • DIC Management and Treatment
                                        • DIC Management Strategies
                                        • Anticoagulant Factor Concentrate Treatment
                                        • Anticoagulant Factor Concentrate Treatment Trials
                                        • Markers of Thrombin amp Plasmin Generation in DIC
                                        • D-dimer FDPs and DIC
                                        • D-Dimer and FDPs in DIC
                                        • Follow Up of DIC State of Disease
                                        • FMD-Dimer in DIC Major Differences
                                        • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                        • Slide Number 85
                                        • Slide Number 86
                                        • Comparing an Automated FM vs Manual FSP Test
                                        • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                        • Diagnostic Performance of FM and D-dimer in DIC
                                        • Diagnostic Performance of FM and D-dimer in DIC
                                        • Diagnostic Performance of FM and D-dimer in DIC
                                        • Diagnostic Performance of FM and D-dimer in DIC
                                        • Diagnostic Performance of FM and D-dimer in DIC
                                        • Slide Number 94
                                        • Slide Number 95
                                        • Slide Number 96
                                        • Slide Number 97
                                        • Slide Number 98
                                        • Slide Number 99
                                        • DIC Case Studies
                                        • Case Study 1 - Presentation
                                        • Case Study 1 ndash Lab Results
                                        • Case Study 1 ndash Microscopy
                                        • Case Study 1 ndash Diagnosis and Therapy
                                        • Slide Number 105
                                        • Slide Number 106
                                        • Slide Number 107
                                        • Slide Number 108
                                        • Slide Number 109
                                        • Slide Number 110
                                        • Slide Number 111
                                        • Slide Number 112
                                        • Slide Number 113
                                        • Slide Number 114
                                        • Slide Number 115
                                        • Slide Number 116
                                        • Slide Number 117
                                        • Slide Number 118
                                        • Slide Number 119
                                        • Slide Number 120
                                        • Slide Number 121
                                        • Slide Number 122
                                        • Slide Number 123
                                        • Slide Number 124
                                        • Slide Number 125
                                        • DIC Take Home Messages
                                        • Slide Number 127
                                        • Slide Number 128

                                          Coagulation Assay Mechanisms

                                          aPTT Based

                                          PT Based

                                          PT Based

                                          Fibrin Under Microscope

                                          Weisel JW Structure of fibrin impact on clot stability J Thromb Haemost 2007 5 Suppl 1 116-24

                                          Low thrombin concentration

                                          High thrombin concentration

                                          Fibrin Formation

                                          Soluble FibrinPolymer

                                          ThrombinFibrinogen

                                          FM+ fibrinopeptides A amp B

                                          Stabilized Fibrin clot(not soluble)

                                          ThrombinXIII XIIIa

                                          (Digestion of Fibrin)

                                          Fibrinolysis

                                          Fibrinolysis Overview

                                          Destroys fibrin fibers

                                          Destroys the scab (dried wound)

                                          Maintains vessel integrity

                                          Fibrinolysis Overview

                                          Fibrin =cement fibers

                                          Plasmin

                                          Plasmin digests fibrin

                                          t-PA

                                          Pro Urokinase

                                          Urokinase

                                          PAI-1PAI-1

                                          Plasminogen Plasmin

                                          1st Step

                                          2nd Step

                                          Fibrinolysis Cascade

                                          t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin

                                          Extrinsic pathway(endothelia l cells)

                                          Intrinsic pathway(plasma)

                                          Fibrin clot

                                          D-dimerFibrin degradation products

                                          Fibrin

                                          TAFIa

                                          APAntiplasmin(amp a2-MG)

                                          PK Kallikrein

                                          XII

                                          Fibrinolysis Releases D-dimers

                                          D-dimer presence fibrin has been formed and digested in patients body

                                          Normal D-dimer level no thrombosis occurred in the patient

                                          Basic Pathophysiology of DIC

                                          Disseminated Intravascular Coagulation (DIC)

                                          Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management

                                          Clinical Manifestations of DICOrgan Ischemic Hemorrhagic

                                          Skin Pupura Fulminans Petechiae

                                          Gangrene Echymoses

                                          Acral cyanosis Oozing

                                          CNS Deliriumcoma Intracranial

                                          Infarcts Bleeding

                                          Renal OliguriaAzotemia Hematuria

                                          Cortical Necrosis

                                          Cardiovascular Myocardial dysfunction

                                          Pulmonary DyspneaHypoxia Hemorrhagic lung

                                          Infarct

                                          Gastrointestinal Ulcers infarcts Massive hemorrhage

                                          Endocrine Adrenal infarcts

                                          Purpura Fulminans with DIC Due to Meningococcal Sepsis

                                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                          Clinical Conditions Associated With DIC

                                          Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                          Frequency of DIC in Selected Disease States

                                          Disease Frequency

                                          Gram-negative sepsis 30-50

                                          Severe trauma and systemic inflammation 50-70

                                          Metastasized tumors 15

                                          Abruptio placentaamniotic fluid embolism 50

                                          Severe preeclampsia 7

                                          Giant hemangioma 25

                                          Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                          Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017

                                          Underlying Diseases in DIC Patients

                                          In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively

                                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                          Epidemiology of DIC

                                          Impact of DIC Status on Mortality - 1

                                          Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8

                                          Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC

                                          Impact of DIC Status on Mortality - 2

                                          Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                          Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients

                                          Impact of Age on Mortality in DIC Patients

                                          Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                          Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)

                                          Pathophysiology of DIC

                                          Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                          Pathogenesis of DIC in Sepsis

                                          Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15

                                          Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC

                                          Host Response in Severe Sepsis

                                          Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral

                                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                          Organ Failure in Severe Sepsis

                                          Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure

                                          Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51

                                          Mechanism of DIC in Organ Failure

                                          Underlying condition(sepsis trauma)

                                          Cytokines

                                          TF-mediatedactivation of coagulation

                                          Depression of inhibitory systems

                                          Reducesfibrinolysis

                                          Fibrin deposition

                                          Organ failure

                                          Inadequate fibrin removal

                                          Fibrinformation

                                          Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )

                                          Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705

                                          Interaction of Inflammation and Coagulation in Sepsis

                                          Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines

                                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                          Mechanism of Multiple Organ Failure in DIC

                                          Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

                                          Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

                                          lipopolysaccharides

                                          cytokines

                                          coagulation activation

                                          mononuclear cell

                                          tissue factor

                                          Diverse and Opposing Effects of Thrombin

                                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                          Coagulation and Fibrinolysis in DIC

                                          Soluble fibrin Polymer

                                          XIIIa

                                          D-Dimer

                                          E

                                          Fibrin clot

                                          Fibrin Degradation Products

                                          Fibrinogen Thrombin

                                          Fibrinogen Degradation

                                          Products

                                          D E

                                          Plasmin

                                          DFM + fibrinopeptides

                                          Soluble FM ComplexesPre-throm

                                          boticPost-throm

                                          botic

                                          Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

                                          Mechanism of DIC

                                          THROMBOSIS

                                          Fibrin

                                          Blood activationEndothelial lysisTF expression

                                          BLEEDING

                                          FDPs

                                          D-Dimer

                                          Plasmin

                                          Pathophysiology of DIC

                                          1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

                                          thromboplastin influx of activated cells (monocytes macrophages)

                                          Results in an intravascular deposition of fibrin

                                          Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

                                          Second step Consumption and depletion of coagulation factors inhibitors (Protein C

                                          Protein S AT) and platelets Local fibrinolytic response

                                          bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

                                          FDP and D-Dimer

                                          Bleeding

                                          Pathophysiology of DIC - Mechanism

                                          Systemic activation of coagulation

                                          Intravasculardepositionof fibrin

                                          Thrombosis of small and midsize vessels

                                          and organ failure

                                          Depletion of platelets and

                                          coagulation factors

                                          Bleeding

                                          Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                          Pathophysiology of DIC ndash 2 Types of Clinical pictures

                                          Chronic = non - overt DICMay be unrecognized clinically

                                          Acute = overt DIClife threatening bleedingor multiple organ failure

                                          Sub-Acute and Non-Overt DIC Clinical Findings

                                          Compensated non-overt DIC Steady low level or intermittent activation

                                          bull Compensated by increased production of coagulation components and platelets

                                          Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                                          Risk of decompensation leading to overt DIC

                                          Pathophysiology of Overt DIC

                                          Massive activation of coagulation and fibrinolysis

                                          Does not allow for compensatory efforts

                                          Rapid depletion of coagulation factors inhibitors and platelets

                                          Thrombosis multiple organ failures

                                          Bleeding complications and shock

                                          Physiopathology of DIC ndash Overt DIC Findings

                                          Thrombin generation

                                          Thrombosis

                                          Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                                          Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                                          Plasmin generationHemorrhage

                                          bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                                          bull Tachycardia hypotension edema

                                          Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                          Pathogenesis Pathways in DIC

                                          Cytokines

                                          TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                                          fibrin inadequateformation fibrin removal

                                          Fibrin deposition

                                          Inflammation

                                          Coagulation

                                          Stago Celebrates Lab Week 2017

                                          NA

                                          Stago 247 Educational Webinar Sites

                                          wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                                          wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                                          Stago Educational Apps

                                          HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                                          iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                                          BREAK

                                          Diagnostic and Management Approach for DIC

                                          Diagnosis of DIC

                                          Clinical diagnosis is obvious in cases of overt DIC

                                          Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                          Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                          Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                          Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                          Important to recognize simultaneous formation of thrombin and plasmin

                                          Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                          Lab Diagnosis of DIC ndash Screening Tests

                                          Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                          Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                          fibrinogen level) repeat testing assesses progression

                                          Screening tests not clinically specific or sensitive for DIC

                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                          Laboratory Changes in Overt DIC

                                          DIC Diagnostic Practices Over Time

                                          Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                          British Journal of Haematology Overt DIC Score

                                          Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                          ISTH Step by Step DIC Algorithm

                                          Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                          US Based Validation of ISTH DIC Score

                                          When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                          Differential Diagnosis in DIC

                                          aHUS atypical hemolytic uremic syndrome

                                          HUS hemolytic uremic syndrome

                                          HIT heparin-induced thrombocytopenia

                                          ITP immune thrombocytopenic purpura

                                          TTP thrombotic thrombocytopenic purpura

                                          DIC and MAHA

                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                          lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                          When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                          DIC Management Goals

                                          Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                          Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                          DIC Management and Treatment

                                          Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                          Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                          requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                          Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                          DIC Management Strategies

                                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                          Anticoagulant Factor Concentrate Treatment

                                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                          Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                          Anticoagulant Factor Concentrate Treatment Trials

                                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                          Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                          Markers of Thrombin amp Plasmin Generation in DIC

                                          D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                          Cut-off value

                                          Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                          degradation products Sensitive assay typically with cutoff adapted for DIC

                                          D-dimer FDPs and DIC

                                          D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                          Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                          Follow Up of DIC State of Disease

                                          Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                          Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                          FMD-Dimer in DIC Major Differences

                                          onset of thrombosis

                                          days

                                          Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                          FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                          D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                          of Abnormal Results in Patients with Confirmed and Suspected DIC

                                          0

                                          20

                                          40

                                          60

                                          80

                                          100

                                          94 85 90N = 62

                                          Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                          Positivity of Test Results ISTH Score and Disease State

                                          Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                          Red bar positive for 2 points of DIC score

                                          Pink bar positive for 1-2 points of DIC score

                                          HT hematopoietic tumor

                                          IF infection

                                          SC solid cancer

                                          Markers in Patients with or without DIC

                                          Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                          HT hematopoietic tumorIF infectionSC solid cancer

                                          Comparing an Automated FM vs Manual FSP Test

                                          Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                          Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                          Automated (Mitsubishi) vs Automated (Stago)

                                          In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                          Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                          Diagnostic Performance of FM and D-dimer in DIC

                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                          Diagnostic Performance of FM and D-dimer in DIC

                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                          In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                          Diagnostic Performance of FM and D-dimer in DIC

                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                          In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                          Diagnostic Performance of FM and D-dimer in DIC

                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                          In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                          Diagnostic Performance of FM and D-dimer in DIC

                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                          Diagnostic Performance of FM and D-dimer in DIC

                                          Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                          No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                          Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                          Diagnostic Performance of FM and D-dimer in DIC

                                          Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                          Non Overt DIC Overt DIC

                                          AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                          Trends in Markers of DIC for Different Patients

                                          Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                          Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                          Trends in Markers of DIC for Different Patients

                                          Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                          FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                          28 day outcome survival

                                          28 day outcome death

                                          Determination of Cutoffs of FM and D-dimer in DIC

                                          Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                          Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                          Determination of Cutoffs of FM and D-dimer in DIC

                                          Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                          Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                          DIC Case Studies

                                          Case Study 1 - Presentation

                                          18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                          Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                          WBC count 77 KμL 423 ndash 907 x KμL

                                          RBC count 17 MμL 137 ndash 175 x MμL

                                          Hemoglobin 67 gdL 137 ndash 175 gdL

                                          Hematocrit 195 401 ndash 510

                                          MCV 95 fL 790 ndash 922 fL

                                          MPV 12 fL 94 ndash 124 fL

                                          Platelet count 9 KμL 161 ndash 347 KμL

                                          Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                          Lymphocytes monocytes eosinophils basophils all below normal range

                                          PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                          APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                          Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                          D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                          Case Study 1 ndash Microscopy

                                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                          Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                          Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                          DIC due to TF release by APL blasts

                                          Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                          Transfusions to replace factors along with platelets and RBCs during APL treatment

                                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                          20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                          Case Study 2 ndash Presentation

                                          TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                          PT 30 sec 113 ndash 146 sec

                                          APTT 75 sec 25 ndash 34 sec

                                          D-dimer 078 microgml FEU lt050 microgml FEU

                                          Fibrinogen 92 mgdl 150-400 mgdl

                                          pH 728 738 to 742

                                          PaO2 570 mmHg 80-100 mmHg

                                          WBC 33 times 103mm3 40-11 times 103mm3

                                          ALT 111 IUL 0ndash34 IUL

                                          AST 61 IUL 0ndash34 IUL

                                          BUN 303 mgdL 08-13 mgdL

                                          Case Study 2 ndash Lab Results

                                          Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                          Case Study 2 ndash Diagnosis

                                          60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                          Case Study 3 ndash Presentation

                                          TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                          PT 228 sec 113 ndash 146 sec

                                          APTT 45 sec 25 ndash 34 sec

                                          D-dimer 080 microgml FEU lt050 microgmL FEU

                                          Fibrinogen 82 mgdL 150-400 mgdL

                                          FV Normal 70-120

                                          FVII Normal 55-170

                                          FVIII Normal 60-150

                                          Protein C Normal 70-130

                                          Hb 134 gdL 14-16 gdL

                                          WBC 81 times 103mm3 40-11 times 103mm3

                                          ALT 32 IUL 0ndash34 IUL

                                          AST 28 IUL 0ndash34 IUL

                                          BUN 09 mgdL 08-13 mgdL

                                          Case Study 3 ndash Lab Results

                                          Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                          Case Study 3 ndash Diagnosis and Therapy

                                          Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                          Case Study 4 ndash Presentation

                                          TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                          PT 28 sec 113 ndash 146 sec

                                          APTT 71 sec 25 ndash 34 sec

                                          D-dimer 31 microgmL FEU lt050 microgml FEU

                                          Fibrinogen 92 mgdL 150-400 mgdl

                                          FV Normal 70-120

                                          FVII Normal 55-170

                                          FVIII Normal 60-150

                                          Protein C Normal 70-130

                                          Hb 158 gdL 14-16 gdL

                                          WBC 71 times 103mm3 40-11 times 103mm3

                                          ALT 60 IUL 0ndash34 IUL

                                          AST 47 IUL 0ndash34 IUL

                                          BUN 38 mgdL 08-13 mgdL

                                          Case Study 4 ndash Lab Results

                                          Lyme disease with DICProvide antibiotics with supportive measures

                                          Case Study 4 ndash Diagnosis

                                          55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                          Case Study 5 ndash Presentation

                                          Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                          Case Study 5 ndash Lab Results and Time Course

                                          Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                          TEST RESULT REFERENCE RANGE

                                          Platelet count 33 x 109L 150-450 x 109L

                                          PT 215 sec 103 ndash 128 sec

                                          APTT 44 sec 26 ndash 36 sec

                                          D-dimer 20 microgmL FEU lt025 microgml FEU

                                          Fibrinogen 34 mgdL 200-375 mgdl

                                          FII FV FVIII Low Not reported (NR)

                                          FVII FIX FX vWF Normal NR

                                          Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                          DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                          dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                          (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                          (D) Illustration demonstrating repair

                                          Case Study 5 ndash Diagnosis and Treatment

                                          Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                          29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                          Case Study 6 ndash Presentation

                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                          Case Study 6 ndash Lab Results

                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                          TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                          PT 63 sec gt control 113 ndash 146 sec

                                          INR 658 1 ndash 125

                                          APTT 80 sec gt control 25 ndash 34 sec

                                          D-dimer gt200 microgmL DDU 02 microgmL DDU

                                          Urine exam Proteinuria and hematuria 150-400 mgdl

                                          Albumin 28 gdL NR

                                          Hb 58 gdL NR

                                          LDH 1196 UL NR

                                          SGPT 144 IU NR

                                          SGOT 88 IU NR

                                          Bilirubin 32 mgdL NR

                                          DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                          day postop

                                          Case Study 6 ndash Diagnosis and Treatment

                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                          HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                          Case Study 6 ndash Discussion

                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                          44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                          Case Study 7 ndash Presentation

                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                          On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                          Case Study 7 ndash Presentation

                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                          Case Study 7 ndash Lab Results vs Time

                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                          Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                          Case Study 7 ndash Diagnosis and Treatment

                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                          On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                          Case Study 7 ndash Diagnosis and Treatment

                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                          DIC Take Home Messages

                                          Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                          Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                          DIC

                                          Thank you Questions

                                          • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                          • Learning Objectives
                                          • Slide Number 3
                                          • Slide Number 4
                                          • Slide Number 5
                                          • Slide Number 6
                                          • Slide Number 7
                                          • Slide Number 8
                                          • Wound Sealing
                                          • The Three Steps of Hemostasis
                                          • Vessel Wall
                                          • Slide Number 12
                                          • Slide Number 13
                                          • Platelet Structure UnactivatedActivated
                                          • Primary Hemostasis
                                          • Primary Hemostasis Assays
                                          • Slide Number 17
                                          • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                          • Slide Number 19
                                          • Coagulation factors
                                          • Coagulation Assay Mechanisms
                                          • Slide Number 22
                                          • Fibrin Formation
                                          • Slide Number 24
                                          • Fibrinolysis Overview
                                          • Fibrinolysis Overview
                                          • Slide Number 27
                                          • Fibrinolysis Releases D-dimers
                                          • Basic Pathophysiology of DIC
                                          • Disseminated Intravascular Coagulation (DIC)
                                          • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                          • Clinical Conditions Associated With DIC
                                          • Frequency of DIC in Selected Disease States
                                          • Underlying Diseases in DIC Patients
                                          • Slide Number 36
                                          • Slide Number 37
                                          • Slide Number 38
                                          • Slide Number 39
                                          • Pathophysiology of DIC
                                          • Pathogenesis of DIC in Sepsis
                                          • Host Response in Severe Sepsis
                                          • Organ Failure in Severe Sepsis
                                          • Mechanism of DIC in Organ Failure
                                          • Interaction of Inflammation and Coagulation in Sepsis
                                          • Slide Number 47
                                          • Diverse and Opposing Effects of Thrombin
                                          • Coagulation and Fibrinolysis in DIC
                                          • Mechanism of DIC
                                          • Pathophysiology of DIC
                                          • Pathophysiology of DIC - Mechanism
                                          • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                          • Sub-Acute and Non-Overt DIC Clinical Findings
                                          • Pathophysiology of Overt DIC
                                          • Physiopathology of DIC ndash Overt DIC Findings
                                          • Slide Number 57
                                          • Slide Number 58
                                          • Slide Number 59
                                          • Slide Number 60
                                          • Slide Number 61
                                          • BREAK
                                          • Diagnostic and Management Approach for DIC
                                          • Diagnosis of DIC
                                          • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                          • Lab Diagnosis of DIC ndash Screening Tests
                                          • Slide Number 67
                                          • Slide Number 68
                                          • British Journal of Haematology Overt DIC Score
                                          • Slide Number 70
                                          • Slide Number 71
                                          • Slide Number 72
                                          • Slide Number 73
                                          • DIC Management Goals
                                          • DIC Management and Treatment
                                          • DIC Management Strategies
                                          • Anticoagulant Factor Concentrate Treatment
                                          • Anticoagulant Factor Concentrate Treatment Trials
                                          • Markers of Thrombin amp Plasmin Generation in DIC
                                          • D-dimer FDPs and DIC
                                          • D-Dimer and FDPs in DIC
                                          • Follow Up of DIC State of Disease
                                          • FMD-Dimer in DIC Major Differences
                                          • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                          • Slide Number 85
                                          • Slide Number 86
                                          • Comparing an Automated FM vs Manual FSP Test
                                          • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                          • Diagnostic Performance of FM and D-dimer in DIC
                                          • Diagnostic Performance of FM and D-dimer in DIC
                                          • Diagnostic Performance of FM and D-dimer in DIC
                                          • Diagnostic Performance of FM and D-dimer in DIC
                                          • Diagnostic Performance of FM and D-dimer in DIC
                                          • Slide Number 94
                                          • Slide Number 95
                                          • Slide Number 96
                                          • Slide Number 97
                                          • Slide Number 98
                                          • Slide Number 99
                                          • DIC Case Studies
                                          • Case Study 1 - Presentation
                                          • Case Study 1 ndash Lab Results
                                          • Case Study 1 ndash Microscopy
                                          • Case Study 1 ndash Diagnosis and Therapy
                                          • Slide Number 105
                                          • Slide Number 106
                                          • Slide Number 107
                                          • Slide Number 108
                                          • Slide Number 109
                                          • Slide Number 110
                                          • Slide Number 111
                                          • Slide Number 112
                                          • Slide Number 113
                                          • Slide Number 114
                                          • Slide Number 115
                                          • Slide Number 116
                                          • Slide Number 117
                                          • Slide Number 118
                                          • Slide Number 119
                                          • Slide Number 120
                                          • Slide Number 121
                                          • Slide Number 122
                                          • Slide Number 123
                                          • Slide Number 124
                                          • Slide Number 125
                                          • DIC Take Home Messages
                                          • Slide Number 127
                                          • Slide Number 128

                                            Fibrin Under Microscope

                                            Weisel JW Structure of fibrin impact on clot stability J Thromb Haemost 2007 5 Suppl 1 116-24

                                            Low thrombin concentration

                                            High thrombin concentration

                                            Fibrin Formation

                                            Soluble FibrinPolymer

                                            ThrombinFibrinogen

                                            FM+ fibrinopeptides A amp B

                                            Stabilized Fibrin clot(not soluble)

                                            ThrombinXIII XIIIa

                                            (Digestion of Fibrin)

                                            Fibrinolysis

                                            Fibrinolysis Overview

                                            Destroys fibrin fibers

                                            Destroys the scab (dried wound)

                                            Maintains vessel integrity

                                            Fibrinolysis Overview

                                            Fibrin =cement fibers

                                            Plasmin

                                            Plasmin digests fibrin

                                            t-PA

                                            Pro Urokinase

                                            Urokinase

                                            PAI-1PAI-1

                                            Plasminogen Plasmin

                                            1st Step

                                            2nd Step

                                            Fibrinolysis Cascade

                                            t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin

                                            Extrinsic pathway(endothelia l cells)

                                            Intrinsic pathway(plasma)

                                            Fibrin clot

                                            D-dimerFibrin degradation products

                                            Fibrin

                                            TAFIa

                                            APAntiplasmin(amp a2-MG)

                                            PK Kallikrein

                                            XII

                                            Fibrinolysis Releases D-dimers

                                            D-dimer presence fibrin has been formed and digested in patients body

                                            Normal D-dimer level no thrombosis occurred in the patient

                                            Basic Pathophysiology of DIC

                                            Disseminated Intravascular Coagulation (DIC)

                                            Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management

                                            Clinical Manifestations of DICOrgan Ischemic Hemorrhagic

                                            Skin Pupura Fulminans Petechiae

                                            Gangrene Echymoses

                                            Acral cyanosis Oozing

                                            CNS Deliriumcoma Intracranial

                                            Infarcts Bleeding

                                            Renal OliguriaAzotemia Hematuria

                                            Cortical Necrosis

                                            Cardiovascular Myocardial dysfunction

                                            Pulmonary DyspneaHypoxia Hemorrhagic lung

                                            Infarct

                                            Gastrointestinal Ulcers infarcts Massive hemorrhage

                                            Endocrine Adrenal infarcts

                                            Purpura Fulminans with DIC Due to Meningococcal Sepsis

                                            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                            Clinical Conditions Associated With DIC

                                            Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                            Frequency of DIC in Selected Disease States

                                            Disease Frequency

                                            Gram-negative sepsis 30-50

                                            Severe trauma and systemic inflammation 50-70

                                            Metastasized tumors 15

                                            Abruptio placentaamniotic fluid embolism 50

                                            Severe preeclampsia 7

                                            Giant hemangioma 25

                                            Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                            Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017

                                            Underlying Diseases in DIC Patients

                                            In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively

                                            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                            Epidemiology of DIC

                                            Impact of DIC Status on Mortality - 1

                                            Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8

                                            Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC

                                            Impact of DIC Status on Mortality - 2

                                            Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                            Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients

                                            Impact of Age on Mortality in DIC Patients

                                            Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                            Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)

                                            Pathophysiology of DIC

                                            Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                            Pathogenesis of DIC in Sepsis

                                            Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15

                                            Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC

                                            Host Response in Severe Sepsis

                                            Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral

                                            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                            Organ Failure in Severe Sepsis

                                            Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure

                                            Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51

                                            Mechanism of DIC in Organ Failure

                                            Underlying condition(sepsis trauma)

                                            Cytokines

                                            TF-mediatedactivation of coagulation

                                            Depression of inhibitory systems

                                            Reducesfibrinolysis

                                            Fibrin deposition

                                            Organ failure

                                            Inadequate fibrin removal

                                            Fibrinformation

                                            Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )

                                            Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705

                                            Interaction of Inflammation and Coagulation in Sepsis

                                            Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines

                                            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                            Mechanism of Multiple Organ Failure in DIC

                                            Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

                                            Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

                                            lipopolysaccharides

                                            cytokines

                                            coagulation activation

                                            mononuclear cell

                                            tissue factor

                                            Diverse and Opposing Effects of Thrombin

                                            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                            Coagulation and Fibrinolysis in DIC

                                            Soluble fibrin Polymer

                                            XIIIa

                                            D-Dimer

                                            E

                                            Fibrin clot

                                            Fibrin Degradation Products

                                            Fibrinogen Thrombin

                                            Fibrinogen Degradation

                                            Products

                                            D E

                                            Plasmin

                                            DFM + fibrinopeptides

                                            Soluble FM ComplexesPre-throm

                                            boticPost-throm

                                            botic

                                            Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

                                            Mechanism of DIC

                                            THROMBOSIS

                                            Fibrin

                                            Blood activationEndothelial lysisTF expression

                                            BLEEDING

                                            FDPs

                                            D-Dimer

                                            Plasmin

                                            Pathophysiology of DIC

                                            1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

                                            thromboplastin influx of activated cells (monocytes macrophages)

                                            Results in an intravascular deposition of fibrin

                                            Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

                                            Second step Consumption and depletion of coagulation factors inhibitors (Protein C

                                            Protein S AT) and platelets Local fibrinolytic response

                                            bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

                                            FDP and D-Dimer

                                            Bleeding

                                            Pathophysiology of DIC - Mechanism

                                            Systemic activation of coagulation

                                            Intravasculardepositionof fibrin

                                            Thrombosis of small and midsize vessels

                                            and organ failure

                                            Depletion of platelets and

                                            coagulation factors

                                            Bleeding

                                            Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                            Pathophysiology of DIC ndash 2 Types of Clinical pictures

                                            Chronic = non - overt DICMay be unrecognized clinically

                                            Acute = overt DIClife threatening bleedingor multiple organ failure

                                            Sub-Acute and Non-Overt DIC Clinical Findings

                                            Compensated non-overt DIC Steady low level or intermittent activation

                                            bull Compensated by increased production of coagulation components and platelets

                                            Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                                            Risk of decompensation leading to overt DIC

                                            Pathophysiology of Overt DIC

                                            Massive activation of coagulation and fibrinolysis

                                            Does not allow for compensatory efforts

                                            Rapid depletion of coagulation factors inhibitors and platelets

                                            Thrombosis multiple organ failures

                                            Bleeding complications and shock

                                            Physiopathology of DIC ndash Overt DIC Findings

                                            Thrombin generation

                                            Thrombosis

                                            Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                                            Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                                            Plasmin generationHemorrhage

                                            bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                                            bull Tachycardia hypotension edema

                                            Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                            Pathogenesis Pathways in DIC

                                            Cytokines

                                            TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                                            fibrin inadequateformation fibrin removal

                                            Fibrin deposition

                                            Inflammation

                                            Coagulation

                                            Stago Celebrates Lab Week 2017

                                            NA

                                            Stago 247 Educational Webinar Sites

                                            wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                                            wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                                            Stago Educational Apps

                                            HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                                            iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                                            BREAK

                                            Diagnostic and Management Approach for DIC

                                            Diagnosis of DIC

                                            Clinical diagnosis is obvious in cases of overt DIC

                                            Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                            Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                            Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                            Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                            Important to recognize simultaneous formation of thrombin and plasmin

                                            Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                            Lab Diagnosis of DIC ndash Screening Tests

                                            Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                            Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                            fibrinogen level) repeat testing assesses progression

                                            Screening tests not clinically specific or sensitive for DIC

                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                            Laboratory Changes in Overt DIC

                                            DIC Diagnostic Practices Over Time

                                            Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                            British Journal of Haematology Overt DIC Score

                                            Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                            ISTH Step by Step DIC Algorithm

                                            Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                            US Based Validation of ISTH DIC Score

                                            When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                            Differential Diagnosis in DIC

                                            aHUS atypical hemolytic uremic syndrome

                                            HUS hemolytic uremic syndrome

                                            HIT heparin-induced thrombocytopenia

                                            ITP immune thrombocytopenic purpura

                                            TTP thrombotic thrombocytopenic purpura

                                            DIC and MAHA

                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                            lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                            When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                            DIC Management Goals

                                            Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                            Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                            DIC Management and Treatment

                                            Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                            Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                            requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                            Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                            DIC Management Strategies

                                            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                            Anticoagulant Factor Concentrate Treatment

                                            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                            Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                            Anticoagulant Factor Concentrate Treatment Trials

                                            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                            Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                            Markers of Thrombin amp Plasmin Generation in DIC

                                            D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                            Cut-off value

                                            Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                            degradation products Sensitive assay typically with cutoff adapted for DIC

                                            D-dimer FDPs and DIC

                                            D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                            Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                            Follow Up of DIC State of Disease

                                            Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                            Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                            FMD-Dimer in DIC Major Differences

                                            onset of thrombosis

                                            days

                                            Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                            FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                            D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                            of Abnormal Results in Patients with Confirmed and Suspected DIC

                                            0

                                            20

                                            40

                                            60

                                            80

                                            100

                                            94 85 90N = 62

                                            Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                            Positivity of Test Results ISTH Score and Disease State

                                            Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                            Red bar positive for 2 points of DIC score

                                            Pink bar positive for 1-2 points of DIC score

                                            HT hematopoietic tumor

                                            IF infection

                                            SC solid cancer

                                            Markers in Patients with or without DIC

                                            Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                            HT hematopoietic tumorIF infectionSC solid cancer

                                            Comparing an Automated FM vs Manual FSP Test

                                            Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                            Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                            Automated (Mitsubishi) vs Automated (Stago)

                                            In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                            Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                            Diagnostic Performance of FM and D-dimer in DIC

                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                            Diagnostic Performance of FM and D-dimer in DIC

                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                            In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                            Diagnostic Performance of FM and D-dimer in DIC

                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                            In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                            Diagnostic Performance of FM and D-dimer in DIC

                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                            In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                            Diagnostic Performance of FM and D-dimer in DIC

                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                            Diagnostic Performance of FM and D-dimer in DIC

                                            Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                            No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                            Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                            Diagnostic Performance of FM and D-dimer in DIC

                                            Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                            Non Overt DIC Overt DIC

                                            AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                            Trends in Markers of DIC for Different Patients

                                            Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                            Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                            Trends in Markers of DIC for Different Patients

                                            Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                            FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                            28 day outcome survival

                                            28 day outcome death

                                            Determination of Cutoffs of FM and D-dimer in DIC

                                            Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                            Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                            Determination of Cutoffs of FM and D-dimer in DIC

                                            Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                            Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                            DIC Case Studies

                                            Case Study 1 - Presentation

                                            18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                            Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                            WBC count 77 KμL 423 ndash 907 x KμL

                                            RBC count 17 MμL 137 ndash 175 x MμL

                                            Hemoglobin 67 gdL 137 ndash 175 gdL

                                            Hematocrit 195 401 ndash 510

                                            MCV 95 fL 790 ndash 922 fL

                                            MPV 12 fL 94 ndash 124 fL

                                            Platelet count 9 KμL 161 ndash 347 KμL

                                            Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                            Lymphocytes monocytes eosinophils basophils all below normal range

                                            PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                            APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                            Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                            D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                            Case Study 1 ndash Microscopy

                                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                            Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                            Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                            DIC due to TF release by APL blasts

                                            Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                            Transfusions to replace factors along with platelets and RBCs during APL treatment

                                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                            20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                            Case Study 2 ndash Presentation

                                            TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                            PT 30 sec 113 ndash 146 sec

                                            APTT 75 sec 25 ndash 34 sec

                                            D-dimer 078 microgml FEU lt050 microgml FEU

                                            Fibrinogen 92 mgdl 150-400 mgdl

                                            pH 728 738 to 742

                                            PaO2 570 mmHg 80-100 mmHg

                                            WBC 33 times 103mm3 40-11 times 103mm3

                                            ALT 111 IUL 0ndash34 IUL

                                            AST 61 IUL 0ndash34 IUL

                                            BUN 303 mgdL 08-13 mgdL

                                            Case Study 2 ndash Lab Results

                                            Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                            Case Study 2 ndash Diagnosis

                                            60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                            Case Study 3 ndash Presentation

                                            TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                            PT 228 sec 113 ndash 146 sec

                                            APTT 45 sec 25 ndash 34 sec

                                            D-dimer 080 microgml FEU lt050 microgmL FEU

                                            Fibrinogen 82 mgdL 150-400 mgdL

                                            FV Normal 70-120

                                            FVII Normal 55-170

                                            FVIII Normal 60-150

                                            Protein C Normal 70-130

                                            Hb 134 gdL 14-16 gdL

                                            WBC 81 times 103mm3 40-11 times 103mm3

                                            ALT 32 IUL 0ndash34 IUL

                                            AST 28 IUL 0ndash34 IUL

                                            BUN 09 mgdL 08-13 mgdL

                                            Case Study 3 ndash Lab Results

                                            Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                            Case Study 3 ndash Diagnosis and Therapy

                                            Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                            Case Study 4 ndash Presentation

                                            TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                            PT 28 sec 113 ndash 146 sec

                                            APTT 71 sec 25 ndash 34 sec

                                            D-dimer 31 microgmL FEU lt050 microgml FEU

                                            Fibrinogen 92 mgdL 150-400 mgdl

                                            FV Normal 70-120

                                            FVII Normal 55-170

                                            FVIII Normal 60-150

                                            Protein C Normal 70-130

                                            Hb 158 gdL 14-16 gdL

                                            WBC 71 times 103mm3 40-11 times 103mm3

                                            ALT 60 IUL 0ndash34 IUL

                                            AST 47 IUL 0ndash34 IUL

                                            BUN 38 mgdL 08-13 mgdL

                                            Case Study 4 ndash Lab Results

                                            Lyme disease with DICProvide antibiotics with supportive measures

                                            Case Study 4 ndash Diagnosis

                                            55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                            Case Study 5 ndash Presentation

                                            Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                            Case Study 5 ndash Lab Results and Time Course

                                            Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                            TEST RESULT REFERENCE RANGE

                                            Platelet count 33 x 109L 150-450 x 109L

                                            PT 215 sec 103 ndash 128 sec

                                            APTT 44 sec 26 ndash 36 sec

                                            D-dimer 20 microgmL FEU lt025 microgml FEU

                                            Fibrinogen 34 mgdL 200-375 mgdl

                                            FII FV FVIII Low Not reported (NR)

                                            FVII FIX FX vWF Normal NR

                                            Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                            DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                            dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                            (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                            (D) Illustration demonstrating repair

                                            Case Study 5 ndash Diagnosis and Treatment

                                            Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                            29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                            Case Study 6 ndash Presentation

                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                            Case Study 6 ndash Lab Results

                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                            TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                            PT 63 sec gt control 113 ndash 146 sec

                                            INR 658 1 ndash 125

                                            APTT 80 sec gt control 25 ndash 34 sec

                                            D-dimer gt200 microgmL DDU 02 microgmL DDU

                                            Urine exam Proteinuria and hematuria 150-400 mgdl

                                            Albumin 28 gdL NR

                                            Hb 58 gdL NR

                                            LDH 1196 UL NR

                                            SGPT 144 IU NR

                                            SGOT 88 IU NR

                                            Bilirubin 32 mgdL NR

                                            DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                            day postop

                                            Case Study 6 ndash Diagnosis and Treatment

                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                            HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                            Case Study 6 ndash Discussion

                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                            44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                            Case Study 7 ndash Presentation

                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                            On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                            Case Study 7 ndash Presentation

                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                            Case Study 7 ndash Lab Results vs Time

                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                            Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                            Case Study 7 ndash Diagnosis and Treatment

                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                            On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                            Case Study 7 ndash Diagnosis and Treatment

                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                            DIC Take Home Messages

                                            Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                            Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                            DIC

                                            Thank you Questions

                                            • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                            • Learning Objectives
                                            • Slide Number 3
                                            • Slide Number 4
                                            • Slide Number 5
                                            • Slide Number 6
                                            • Slide Number 7
                                            • Slide Number 8
                                            • Wound Sealing
                                            • The Three Steps of Hemostasis
                                            • Vessel Wall
                                            • Slide Number 12
                                            • Slide Number 13
                                            • Platelet Structure UnactivatedActivated
                                            • Primary Hemostasis
                                            • Primary Hemostasis Assays
                                            • Slide Number 17
                                            • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                            • Slide Number 19
                                            • Coagulation factors
                                            • Coagulation Assay Mechanisms
                                            • Slide Number 22
                                            • Fibrin Formation
                                            • Slide Number 24
                                            • Fibrinolysis Overview
                                            • Fibrinolysis Overview
                                            • Slide Number 27
                                            • Fibrinolysis Releases D-dimers
                                            • Basic Pathophysiology of DIC
                                            • Disseminated Intravascular Coagulation (DIC)
                                            • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                            • Clinical Conditions Associated With DIC
                                            • Frequency of DIC in Selected Disease States
                                            • Underlying Diseases in DIC Patients
                                            • Slide Number 36
                                            • Slide Number 37
                                            • Slide Number 38
                                            • Slide Number 39
                                            • Pathophysiology of DIC
                                            • Pathogenesis of DIC in Sepsis
                                            • Host Response in Severe Sepsis
                                            • Organ Failure in Severe Sepsis
                                            • Mechanism of DIC in Organ Failure
                                            • Interaction of Inflammation and Coagulation in Sepsis
                                            • Slide Number 47
                                            • Diverse and Opposing Effects of Thrombin
                                            • Coagulation and Fibrinolysis in DIC
                                            • Mechanism of DIC
                                            • Pathophysiology of DIC
                                            • Pathophysiology of DIC - Mechanism
                                            • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                            • Sub-Acute and Non-Overt DIC Clinical Findings
                                            • Pathophysiology of Overt DIC
                                            • Physiopathology of DIC ndash Overt DIC Findings
                                            • Slide Number 57
                                            • Slide Number 58
                                            • Slide Number 59
                                            • Slide Number 60
                                            • Slide Number 61
                                            • BREAK
                                            • Diagnostic and Management Approach for DIC
                                            • Diagnosis of DIC
                                            • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                            • Lab Diagnosis of DIC ndash Screening Tests
                                            • Slide Number 67
                                            • Slide Number 68
                                            • British Journal of Haematology Overt DIC Score
                                            • Slide Number 70
                                            • Slide Number 71
                                            • Slide Number 72
                                            • Slide Number 73
                                            • DIC Management Goals
                                            • DIC Management and Treatment
                                            • DIC Management Strategies
                                            • Anticoagulant Factor Concentrate Treatment
                                            • Anticoagulant Factor Concentrate Treatment Trials
                                            • Markers of Thrombin amp Plasmin Generation in DIC
                                            • D-dimer FDPs and DIC
                                            • D-Dimer and FDPs in DIC
                                            • Follow Up of DIC State of Disease
                                            • FMD-Dimer in DIC Major Differences
                                            • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                            • Slide Number 85
                                            • Slide Number 86
                                            • Comparing an Automated FM vs Manual FSP Test
                                            • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                            • Diagnostic Performance of FM and D-dimer in DIC
                                            • Diagnostic Performance of FM and D-dimer in DIC
                                            • Diagnostic Performance of FM and D-dimer in DIC
                                            • Diagnostic Performance of FM and D-dimer in DIC
                                            • Diagnostic Performance of FM and D-dimer in DIC
                                            • Slide Number 94
                                            • Slide Number 95
                                            • Slide Number 96
                                            • Slide Number 97
                                            • Slide Number 98
                                            • Slide Number 99
                                            • DIC Case Studies
                                            • Case Study 1 - Presentation
                                            • Case Study 1 ndash Lab Results
                                            • Case Study 1 ndash Microscopy
                                            • Case Study 1 ndash Diagnosis and Therapy
                                            • Slide Number 105
                                            • Slide Number 106
                                            • Slide Number 107
                                            • Slide Number 108
                                            • Slide Number 109
                                            • Slide Number 110
                                            • Slide Number 111
                                            • Slide Number 112
                                            • Slide Number 113
                                            • Slide Number 114
                                            • Slide Number 115
                                            • Slide Number 116
                                            • Slide Number 117
                                            • Slide Number 118
                                            • Slide Number 119
                                            • Slide Number 120
                                            • Slide Number 121
                                            • Slide Number 122
                                            • Slide Number 123
                                            • Slide Number 124
                                            • Slide Number 125
                                            • DIC Take Home Messages
                                            • Slide Number 127
                                            • Slide Number 128

                                              Fibrin Formation

                                              Soluble FibrinPolymer

                                              ThrombinFibrinogen

                                              FM+ fibrinopeptides A amp B

                                              Stabilized Fibrin clot(not soluble)

                                              ThrombinXIII XIIIa

                                              (Digestion of Fibrin)

                                              Fibrinolysis

                                              Fibrinolysis Overview

                                              Destroys fibrin fibers

                                              Destroys the scab (dried wound)

                                              Maintains vessel integrity

                                              Fibrinolysis Overview

                                              Fibrin =cement fibers

                                              Plasmin

                                              Plasmin digests fibrin

                                              t-PA

                                              Pro Urokinase

                                              Urokinase

                                              PAI-1PAI-1

                                              Plasminogen Plasmin

                                              1st Step

                                              2nd Step

                                              Fibrinolysis Cascade

                                              t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin

                                              Extrinsic pathway(endothelia l cells)

                                              Intrinsic pathway(plasma)

                                              Fibrin clot

                                              D-dimerFibrin degradation products

                                              Fibrin

                                              TAFIa

                                              APAntiplasmin(amp a2-MG)

                                              PK Kallikrein

                                              XII

                                              Fibrinolysis Releases D-dimers

                                              D-dimer presence fibrin has been formed and digested in patients body

                                              Normal D-dimer level no thrombosis occurred in the patient

                                              Basic Pathophysiology of DIC

                                              Disseminated Intravascular Coagulation (DIC)

                                              Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management

                                              Clinical Manifestations of DICOrgan Ischemic Hemorrhagic

                                              Skin Pupura Fulminans Petechiae

                                              Gangrene Echymoses

                                              Acral cyanosis Oozing

                                              CNS Deliriumcoma Intracranial

                                              Infarcts Bleeding

                                              Renal OliguriaAzotemia Hematuria

                                              Cortical Necrosis

                                              Cardiovascular Myocardial dysfunction

                                              Pulmonary DyspneaHypoxia Hemorrhagic lung

                                              Infarct

                                              Gastrointestinal Ulcers infarcts Massive hemorrhage

                                              Endocrine Adrenal infarcts

                                              Purpura Fulminans with DIC Due to Meningococcal Sepsis

                                              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                              Clinical Conditions Associated With DIC

                                              Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                              Frequency of DIC in Selected Disease States

                                              Disease Frequency

                                              Gram-negative sepsis 30-50

                                              Severe trauma and systemic inflammation 50-70

                                              Metastasized tumors 15

                                              Abruptio placentaamniotic fluid embolism 50

                                              Severe preeclampsia 7

                                              Giant hemangioma 25

                                              Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                              Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017

                                              Underlying Diseases in DIC Patients

                                              In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively

                                              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                              Epidemiology of DIC

                                              Impact of DIC Status on Mortality - 1

                                              Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8

                                              Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC

                                              Impact of DIC Status on Mortality - 2

                                              Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                              Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients

                                              Impact of Age on Mortality in DIC Patients

                                              Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                              Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)

                                              Pathophysiology of DIC

                                              Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                              Pathogenesis of DIC in Sepsis

                                              Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15

                                              Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC

                                              Host Response in Severe Sepsis

                                              Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral

                                              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                              Organ Failure in Severe Sepsis

                                              Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure

                                              Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51

                                              Mechanism of DIC in Organ Failure

                                              Underlying condition(sepsis trauma)

                                              Cytokines

                                              TF-mediatedactivation of coagulation

                                              Depression of inhibitory systems

                                              Reducesfibrinolysis

                                              Fibrin deposition

                                              Organ failure

                                              Inadequate fibrin removal

                                              Fibrinformation

                                              Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )

                                              Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705

                                              Interaction of Inflammation and Coagulation in Sepsis

                                              Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines

                                              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                              Mechanism of Multiple Organ Failure in DIC

                                              Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

                                              Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

                                              lipopolysaccharides

                                              cytokines

                                              coagulation activation

                                              mononuclear cell

                                              tissue factor

                                              Diverse and Opposing Effects of Thrombin

                                              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                              Coagulation and Fibrinolysis in DIC

                                              Soluble fibrin Polymer

                                              XIIIa

                                              D-Dimer

                                              E

                                              Fibrin clot

                                              Fibrin Degradation Products

                                              Fibrinogen Thrombin

                                              Fibrinogen Degradation

                                              Products

                                              D E

                                              Plasmin

                                              DFM + fibrinopeptides

                                              Soluble FM ComplexesPre-throm

                                              boticPost-throm

                                              botic

                                              Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

                                              Mechanism of DIC

                                              THROMBOSIS

                                              Fibrin

                                              Blood activationEndothelial lysisTF expression

                                              BLEEDING

                                              FDPs

                                              D-Dimer

                                              Plasmin

                                              Pathophysiology of DIC

                                              1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

                                              thromboplastin influx of activated cells (monocytes macrophages)

                                              Results in an intravascular deposition of fibrin

                                              Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

                                              Second step Consumption and depletion of coagulation factors inhibitors (Protein C

                                              Protein S AT) and platelets Local fibrinolytic response

                                              bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

                                              FDP and D-Dimer

                                              Bleeding

                                              Pathophysiology of DIC - Mechanism

                                              Systemic activation of coagulation

                                              Intravasculardepositionof fibrin

                                              Thrombosis of small and midsize vessels

                                              and organ failure

                                              Depletion of platelets and

                                              coagulation factors

                                              Bleeding

                                              Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                              Pathophysiology of DIC ndash 2 Types of Clinical pictures

                                              Chronic = non - overt DICMay be unrecognized clinically

                                              Acute = overt DIClife threatening bleedingor multiple organ failure

                                              Sub-Acute and Non-Overt DIC Clinical Findings

                                              Compensated non-overt DIC Steady low level or intermittent activation

                                              bull Compensated by increased production of coagulation components and platelets

                                              Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                                              Risk of decompensation leading to overt DIC

                                              Pathophysiology of Overt DIC

                                              Massive activation of coagulation and fibrinolysis

                                              Does not allow for compensatory efforts

                                              Rapid depletion of coagulation factors inhibitors and platelets

                                              Thrombosis multiple organ failures

                                              Bleeding complications and shock

                                              Physiopathology of DIC ndash Overt DIC Findings

                                              Thrombin generation

                                              Thrombosis

                                              Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                                              Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                                              Plasmin generationHemorrhage

                                              bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                                              bull Tachycardia hypotension edema

                                              Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                              Pathogenesis Pathways in DIC

                                              Cytokines

                                              TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                                              fibrin inadequateformation fibrin removal

                                              Fibrin deposition

                                              Inflammation

                                              Coagulation

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                                              BREAK

                                              Diagnostic and Management Approach for DIC

                                              Diagnosis of DIC

                                              Clinical diagnosis is obvious in cases of overt DIC

                                              Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                              Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                              Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                              Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                              Important to recognize simultaneous formation of thrombin and plasmin

                                              Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                              Lab Diagnosis of DIC ndash Screening Tests

                                              Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                              Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                              fibrinogen level) repeat testing assesses progression

                                              Screening tests not clinically specific or sensitive for DIC

                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                              Laboratory Changes in Overt DIC

                                              DIC Diagnostic Practices Over Time

                                              Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                              British Journal of Haematology Overt DIC Score

                                              Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                              ISTH Step by Step DIC Algorithm

                                              Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                              US Based Validation of ISTH DIC Score

                                              When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                              Differential Diagnosis in DIC

                                              aHUS atypical hemolytic uremic syndrome

                                              HUS hemolytic uremic syndrome

                                              HIT heparin-induced thrombocytopenia

                                              ITP immune thrombocytopenic purpura

                                              TTP thrombotic thrombocytopenic purpura

                                              DIC and MAHA

                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                              lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                              When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                              DIC Management Goals

                                              Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                              Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                              DIC Management and Treatment

                                              Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                              Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                              requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                              Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                              DIC Management Strategies

                                              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                              Anticoagulant Factor Concentrate Treatment

                                              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                              Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                              Anticoagulant Factor Concentrate Treatment Trials

                                              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                              Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                              Markers of Thrombin amp Plasmin Generation in DIC

                                              D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                              Cut-off value

                                              Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                              degradation products Sensitive assay typically with cutoff adapted for DIC

                                              D-dimer FDPs and DIC

                                              D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                              Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                              Follow Up of DIC State of Disease

                                              Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                              Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                              FMD-Dimer in DIC Major Differences

                                              onset of thrombosis

                                              days

                                              Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                              FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                              D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                              of Abnormal Results in Patients with Confirmed and Suspected DIC

                                              0

                                              20

                                              40

                                              60

                                              80

                                              100

                                              94 85 90N = 62

                                              Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                              Positivity of Test Results ISTH Score and Disease State

                                              Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                              Red bar positive for 2 points of DIC score

                                              Pink bar positive for 1-2 points of DIC score

                                              HT hematopoietic tumor

                                              IF infection

                                              SC solid cancer

                                              Markers in Patients with or without DIC

                                              Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                              HT hematopoietic tumorIF infectionSC solid cancer

                                              Comparing an Automated FM vs Manual FSP Test

                                              Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                              Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                              Automated (Mitsubishi) vs Automated (Stago)

                                              In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                              Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                              Diagnostic Performance of FM and D-dimer in DIC

                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                              Diagnostic Performance of FM and D-dimer in DIC

                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                              In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                              Diagnostic Performance of FM and D-dimer in DIC

                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                              In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                              Diagnostic Performance of FM and D-dimer in DIC

                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                              In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                              Diagnostic Performance of FM and D-dimer in DIC

                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                              Diagnostic Performance of FM and D-dimer in DIC

                                              Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                              No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                              Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                              Diagnostic Performance of FM and D-dimer in DIC

                                              Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                              Non Overt DIC Overt DIC

                                              AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                              Trends in Markers of DIC for Different Patients

                                              Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                              Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                              Trends in Markers of DIC for Different Patients

                                              Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                              FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                              28 day outcome survival

                                              28 day outcome death

                                              Determination of Cutoffs of FM and D-dimer in DIC

                                              Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                              Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                              Determination of Cutoffs of FM and D-dimer in DIC

                                              Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                              Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                              DIC Case Studies

                                              Case Study 1 - Presentation

                                              18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                              Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                              WBC count 77 KμL 423 ndash 907 x KμL

                                              RBC count 17 MμL 137 ndash 175 x MμL

                                              Hemoglobin 67 gdL 137 ndash 175 gdL

                                              Hematocrit 195 401 ndash 510

                                              MCV 95 fL 790 ndash 922 fL

                                              MPV 12 fL 94 ndash 124 fL

                                              Platelet count 9 KμL 161 ndash 347 KμL

                                              Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                              Lymphocytes monocytes eosinophils basophils all below normal range

                                              PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                              APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                              Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                              D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                              Case Study 1 ndash Microscopy

                                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                              Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                              Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                              DIC due to TF release by APL blasts

                                              Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                              Transfusions to replace factors along with platelets and RBCs during APL treatment

                                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                              20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                              Case Study 2 ndash Presentation

                                              TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                              PT 30 sec 113 ndash 146 sec

                                              APTT 75 sec 25 ndash 34 sec

                                              D-dimer 078 microgml FEU lt050 microgml FEU

                                              Fibrinogen 92 mgdl 150-400 mgdl

                                              pH 728 738 to 742

                                              PaO2 570 mmHg 80-100 mmHg

                                              WBC 33 times 103mm3 40-11 times 103mm3

                                              ALT 111 IUL 0ndash34 IUL

                                              AST 61 IUL 0ndash34 IUL

                                              BUN 303 mgdL 08-13 mgdL

                                              Case Study 2 ndash Lab Results

                                              Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                              Case Study 2 ndash Diagnosis

                                              60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                              Case Study 3 ndash Presentation

                                              TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                              PT 228 sec 113 ndash 146 sec

                                              APTT 45 sec 25 ndash 34 sec

                                              D-dimer 080 microgml FEU lt050 microgmL FEU

                                              Fibrinogen 82 mgdL 150-400 mgdL

                                              FV Normal 70-120

                                              FVII Normal 55-170

                                              FVIII Normal 60-150

                                              Protein C Normal 70-130

                                              Hb 134 gdL 14-16 gdL

                                              WBC 81 times 103mm3 40-11 times 103mm3

                                              ALT 32 IUL 0ndash34 IUL

                                              AST 28 IUL 0ndash34 IUL

                                              BUN 09 mgdL 08-13 mgdL

                                              Case Study 3 ndash Lab Results

                                              Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                              Case Study 3 ndash Diagnosis and Therapy

                                              Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                              Case Study 4 ndash Presentation

                                              TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                              PT 28 sec 113 ndash 146 sec

                                              APTT 71 sec 25 ndash 34 sec

                                              D-dimer 31 microgmL FEU lt050 microgml FEU

                                              Fibrinogen 92 mgdL 150-400 mgdl

                                              FV Normal 70-120

                                              FVII Normal 55-170

                                              FVIII Normal 60-150

                                              Protein C Normal 70-130

                                              Hb 158 gdL 14-16 gdL

                                              WBC 71 times 103mm3 40-11 times 103mm3

                                              ALT 60 IUL 0ndash34 IUL

                                              AST 47 IUL 0ndash34 IUL

                                              BUN 38 mgdL 08-13 mgdL

                                              Case Study 4 ndash Lab Results

                                              Lyme disease with DICProvide antibiotics with supportive measures

                                              Case Study 4 ndash Diagnosis

                                              55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                              Case Study 5 ndash Presentation

                                              Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                              Case Study 5 ndash Lab Results and Time Course

                                              Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                              TEST RESULT REFERENCE RANGE

                                              Platelet count 33 x 109L 150-450 x 109L

                                              PT 215 sec 103 ndash 128 sec

                                              APTT 44 sec 26 ndash 36 sec

                                              D-dimer 20 microgmL FEU lt025 microgml FEU

                                              Fibrinogen 34 mgdL 200-375 mgdl

                                              FII FV FVIII Low Not reported (NR)

                                              FVII FIX FX vWF Normal NR

                                              Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                              DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                              dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                              (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                              (D) Illustration demonstrating repair

                                              Case Study 5 ndash Diagnosis and Treatment

                                              Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                              29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                              Case Study 6 ndash Presentation

                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                              Case Study 6 ndash Lab Results

                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                              TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                              PT 63 sec gt control 113 ndash 146 sec

                                              INR 658 1 ndash 125

                                              APTT 80 sec gt control 25 ndash 34 sec

                                              D-dimer gt200 microgmL DDU 02 microgmL DDU

                                              Urine exam Proteinuria and hematuria 150-400 mgdl

                                              Albumin 28 gdL NR

                                              Hb 58 gdL NR

                                              LDH 1196 UL NR

                                              SGPT 144 IU NR

                                              SGOT 88 IU NR

                                              Bilirubin 32 mgdL NR

                                              DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                              day postop

                                              Case Study 6 ndash Diagnosis and Treatment

                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                              HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                              Case Study 6 ndash Discussion

                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                              44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                              Case Study 7 ndash Presentation

                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                              On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                              Case Study 7 ndash Presentation

                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                              Case Study 7 ndash Lab Results vs Time

                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                              Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                              Case Study 7 ndash Diagnosis and Treatment

                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                              On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                              Case Study 7 ndash Diagnosis and Treatment

                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                              DIC Take Home Messages

                                              Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                              Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                              DIC

                                              Thank you Questions

                                              • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                              • Learning Objectives
                                              • Slide Number 3
                                              • Slide Number 4
                                              • Slide Number 5
                                              • Slide Number 6
                                              • Slide Number 7
                                              • Slide Number 8
                                              • Wound Sealing
                                              • The Three Steps of Hemostasis
                                              • Vessel Wall
                                              • Slide Number 12
                                              • Slide Number 13
                                              • Platelet Structure UnactivatedActivated
                                              • Primary Hemostasis
                                              • Primary Hemostasis Assays
                                              • Slide Number 17
                                              • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                              • Slide Number 19
                                              • Coagulation factors
                                              • Coagulation Assay Mechanisms
                                              • Slide Number 22
                                              • Fibrin Formation
                                              • Slide Number 24
                                              • Fibrinolysis Overview
                                              • Fibrinolysis Overview
                                              • Slide Number 27
                                              • Fibrinolysis Releases D-dimers
                                              • Basic Pathophysiology of DIC
                                              • Disseminated Intravascular Coagulation (DIC)
                                              • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                              • Clinical Conditions Associated With DIC
                                              • Frequency of DIC in Selected Disease States
                                              • Underlying Diseases in DIC Patients
                                              • Slide Number 36
                                              • Slide Number 37
                                              • Slide Number 38
                                              • Slide Number 39
                                              • Pathophysiology of DIC
                                              • Pathogenesis of DIC in Sepsis
                                              • Host Response in Severe Sepsis
                                              • Organ Failure in Severe Sepsis
                                              • Mechanism of DIC in Organ Failure
                                              • Interaction of Inflammation and Coagulation in Sepsis
                                              • Slide Number 47
                                              • Diverse and Opposing Effects of Thrombin
                                              • Coagulation and Fibrinolysis in DIC
                                              • Mechanism of DIC
                                              • Pathophysiology of DIC
                                              • Pathophysiology of DIC - Mechanism
                                              • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                              • Sub-Acute and Non-Overt DIC Clinical Findings
                                              • Pathophysiology of Overt DIC
                                              • Physiopathology of DIC ndash Overt DIC Findings
                                              • Slide Number 57
                                              • Slide Number 58
                                              • Slide Number 59
                                              • Slide Number 60
                                              • Slide Number 61
                                              • BREAK
                                              • Diagnostic and Management Approach for DIC
                                              • Diagnosis of DIC
                                              • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                              • Lab Diagnosis of DIC ndash Screening Tests
                                              • Slide Number 67
                                              • Slide Number 68
                                              • British Journal of Haematology Overt DIC Score
                                              • Slide Number 70
                                              • Slide Number 71
                                              • Slide Number 72
                                              • Slide Number 73
                                              • DIC Management Goals
                                              • DIC Management and Treatment
                                              • DIC Management Strategies
                                              • Anticoagulant Factor Concentrate Treatment
                                              • Anticoagulant Factor Concentrate Treatment Trials
                                              • Markers of Thrombin amp Plasmin Generation in DIC
                                              • D-dimer FDPs and DIC
                                              • D-Dimer and FDPs in DIC
                                              • Follow Up of DIC State of Disease
                                              • FMD-Dimer in DIC Major Differences
                                              • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                              • Slide Number 85
                                              • Slide Number 86
                                              • Comparing an Automated FM vs Manual FSP Test
                                              • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                              • Diagnostic Performance of FM and D-dimer in DIC
                                              • Diagnostic Performance of FM and D-dimer in DIC
                                              • Diagnostic Performance of FM and D-dimer in DIC
                                              • Diagnostic Performance of FM and D-dimer in DIC
                                              • Diagnostic Performance of FM and D-dimer in DIC
                                              • Slide Number 94
                                              • Slide Number 95
                                              • Slide Number 96
                                              • Slide Number 97
                                              • Slide Number 98
                                              • Slide Number 99
                                              • DIC Case Studies
                                              • Case Study 1 - Presentation
                                              • Case Study 1 ndash Lab Results
                                              • Case Study 1 ndash Microscopy
                                              • Case Study 1 ndash Diagnosis and Therapy
                                              • Slide Number 105
                                              • Slide Number 106
                                              • Slide Number 107
                                              • Slide Number 108
                                              • Slide Number 109
                                              • Slide Number 110
                                              • Slide Number 111
                                              • Slide Number 112
                                              • Slide Number 113
                                              • Slide Number 114
                                              • Slide Number 115
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                                              • Slide Number 120
                                              • Slide Number 121
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                                              • Slide Number 123
                                              • Slide Number 124
                                              • Slide Number 125
                                              • DIC Take Home Messages
                                              • Slide Number 127
                                              • Slide Number 128

                                                (Digestion of Fibrin)

                                                Fibrinolysis

                                                Fibrinolysis Overview

                                                Destroys fibrin fibers

                                                Destroys the scab (dried wound)

                                                Maintains vessel integrity

                                                Fibrinolysis Overview

                                                Fibrin =cement fibers

                                                Plasmin

                                                Plasmin digests fibrin

                                                t-PA

                                                Pro Urokinase

                                                Urokinase

                                                PAI-1PAI-1

                                                Plasminogen Plasmin

                                                1st Step

                                                2nd Step

                                                Fibrinolysis Cascade

                                                t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin

                                                Extrinsic pathway(endothelia l cells)

                                                Intrinsic pathway(plasma)

                                                Fibrin clot

                                                D-dimerFibrin degradation products

                                                Fibrin

                                                TAFIa

                                                APAntiplasmin(amp a2-MG)

                                                PK Kallikrein

                                                XII

                                                Fibrinolysis Releases D-dimers

                                                D-dimer presence fibrin has been formed and digested in patients body

                                                Normal D-dimer level no thrombosis occurred in the patient

                                                Basic Pathophysiology of DIC

                                                Disseminated Intravascular Coagulation (DIC)

                                                Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management

                                                Clinical Manifestations of DICOrgan Ischemic Hemorrhagic

                                                Skin Pupura Fulminans Petechiae

                                                Gangrene Echymoses

                                                Acral cyanosis Oozing

                                                CNS Deliriumcoma Intracranial

                                                Infarcts Bleeding

                                                Renal OliguriaAzotemia Hematuria

                                                Cortical Necrosis

                                                Cardiovascular Myocardial dysfunction

                                                Pulmonary DyspneaHypoxia Hemorrhagic lung

                                                Infarct

                                                Gastrointestinal Ulcers infarcts Massive hemorrhage

                                                Endocrine Adrenal infarcts

                                                Purpura Fulminans with DIC Due to Meningococcal Sepsis

                                                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                Clinical Conditions Associated With DIC

                                                Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                Frequency of DIC in Selected Disease States

                                                Disease Frequency

                                                Gram-negative sepsis 30-50

                                                Severe trauma and systemic inflammation 50-70

                                                Metastasized tumors 15

                                                Abruptio placentaamniotic fluid embolism 50

                                                Severe preeclampsia 7

                                                Giant hemangioma 25

                                                Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                                Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017

                                                Underlying Diseases in DIC Patients

                                                In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively

                                                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                Epidemiology of DIC

                                                Impact of DIC Status on Mortality - 1

                                                Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8

                                                Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC

                                                Impact of DIC Status on Mortality - 2

                                                Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                                Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients

                                                Impact of Age on Mortality in DIC Patients

                                                Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                                Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)

                                                Pathophysiology of DIC

                                                Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                Pathogenesis of DIC in Sepsis

                                                Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15

                                                Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC

                                                Host Response in Severe Sepsis

                                                Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral

                                                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                Organ Failure in Severe Sepsis

                                                Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure

                                                Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51

                                                Mechanism of DIC in Organ Failure

                                                Underlying condition(sepsis trauma)

                                                Cytokines

                                                TF-mediatedactivation of coagulation

                                                Depression of inhibitory systems

                                                Reducesfibrinolysis

                                                Fibrin deposition

                                                Organ failure

                                                Inadequate fibrin removal

                                                Fibrinformation

                                                Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )

                                                Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705

                                                Interaction of Inflammation and Coagulation in Sepsis

                                                Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines

                                                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                Mechanism of Multiple Organ Failure in DIC

                                                Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

                                                Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

                                                lipopolysaccharides

                                                cytokines

                                                coagulation activation

                                                mononuclear cell

                                                tissue factor

                                                Diverse and Opposing Effects of Thrombin

                                                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                Coagulation and Fibrinolysis in DIC

                                                Soluble fibrin Polymer

                                                XIIIa

                                                D-Dimer

                                                E

                                                Fibrin clot

                                                Fibrin Degradation Products

                                                Fibrinogen Thrombin

                                                Fibrinogen Degradation

                                                Products

                                                D E

                                                Plasmin

                                                DFM + fibrinopeptides

                                                Soluble FM ComplexesPre-throm

                                                boticPost-throm

                                                botic

                                                Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

                                                Mechanism of DIC

                                                THROMBOSIS

                                                Fibrin

                                                Blood activationEndothelial lysisTF expression

                                                BLEEDING

                                                FDPs

                                                D-Dimer

                                                Plasmin

                                                Pathophysiology of DIC

                                                1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

                                                thromboplastin influx of activated cells (monocytes macrophages)

                                                Results in an intravascular deposition of fibrin

                                                Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

                                                Second step Consumption and depletion of coagulation factors inhibitors (Protein C

                                                Protein S AT) and platelets Local fibrinolytic response

                                                bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

                                                FDP and D-Dimer

                                                Bleeding

                                                Pathophysiology of DIC - Mechanism

                                                Systemic activation of coagulation

                                                Intravasculardepositionof fibrin

                                                Thrombosis of small and midsize vessels

                                                and organ failure

                                                Depletion of platelets and

                                                coagulation factors

                                                Bleeding

                                                Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                                Pathophysiology of DIC ndash 2 Types of Clinical pictures

                                                Chronic = non - overt DICMay be unrecognized clinically

                                                Acute = overt DIClife threatening bleedingor multiple organ failure

                                                Sub-Acute and Non-Overt DIC Clinical Findings

                                                Compensated non-overt DIC Steady low level or intermittent activation

                                                bull Compensated by increased production of coagulation components and platelets

                                                Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                                                Risk of decompensation leading to overt DIC

                                                Pathophysiology of Overt DIC

                                                Massive activation of coagulation and fibrinolysis

                                                Does not allow for compensatory efforts

                                                Rapid depletion of coagulation factors inhibitors and platelets

                                                Thrombosis multiple organ failures

                                                Bleeding complications and shock

                                                Physiopathology of DIC ndash Overt DIC Findings

                                                Thrombin generation

                                                Thrombosis

                                                Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                                                Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                                                Plasmin generationHemorrhage

                                                bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                                                bull Tachycardia hypotension edema

                                                Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                Pathogenesis Pathways in DIC

                                                Cytokines

                                                TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                                                fibrin inadequateformation fibrin removal

                                                Fibrin deposition

                                                Inflammation

                                                Coagulation

                                                Stago Celebrates Lab Week 2017

                                                NA

                                                Stago 247 Educational Webinar Sites

                                                wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                                                wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                                                Stago Educational Apps

                                                HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                                                iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                                                BREAK

                                                Diagnostic and Management Approach for DIC

                                                Diagnosis of DIC

                                                Clinical diagnosis is obvious in cases of overt DIC

                                                Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                                Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                                Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                                Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                                Important to recognize simultaneous formation of thrombin and plasmin

                                                Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                Lab Diagnosis of DIC ndash Screening Tests

                                                Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                                fibrinogen level) repeat testing assesses progression

                                                Screening tests not clinically specific or sensitive for DIC

                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                Laboratory Changes in Overt DIC

                                                DIC Diagnostic Practices Over Time

                                                Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                British Journal of Haematology Overt DIC Score

                                                Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                ISTH Step by Step DIC Algorithm

                                                Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                US Based Validation of ISTH DIC Score

                                                When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                Differential Diagnosis in DIC

                                                aHUS atypical hemolytic uremic syndrome

                                                HUS hemolytic uremic syndrome

                                                HIT heparin-induced thrombocytopenia

                                                ITP immune thrombocytopenic purpura

                                                TTP thrombotic thrombocytopenic purpura

                                                DIC and MAHA

                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                DIC Management Goals

                                                Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                DIC Management and Treatment

                                                Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                DIC Management Strategies

                                                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                Anticoagulant Factor Concentrate Treatment

                                                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                Anticoagulant Factor Concentrate Treatment Trials

                                                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                Markers of Thrombin amp Plasmin Generation in DIC

                                                D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                Cut-off value

                                                Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                degradation products Sensitive assay typically with cutoff adapted for DIC

                                                D-dimer FDPs and DIC

                                                D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                Follow Up of DIC State of Disease

                                                Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                FMD-Dimer in DIC Major Differences

                                                onset of thrombosis

                                                days

                                                Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                0

                                                20

                                                40

                                                60

                                                80

                                                100

                                                94 85 90N = 62

                                                Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                Positivity of Test Results ISTH Score and Disease State

                                                Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                Red bar positive for 2 points of DIC score

                                                Pink bar positive for 1-2 points of DIC score

                                                HT hematopoietic tumor

                                                IF infection

                                                SC solid cancer

                                                Markers in Patients with or without DIC

                                                Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                HT hematopoietic tumorIF infectionSC solid cancer

                                                Comparing an Automated FM vs Manual FSP Test

                                                Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                Automated (Mitsubishi) vs Automated (Stago)

                                                In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                Diagnostic Performance of FM and D-dimer in DIC

                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                Diagnostic Performance of FM and D-dimer in DIC

                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                Diagnostic Performance of FM and D-dimer in DIC

                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                Diagnostic Performance of FM and D-dimer in DIC

                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                Diagnostic Performance of FM and D-dimer in DIC

                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                Diagnostic Performance of FM and D-dimer in DIC

                                                Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                Diagnostic Performance of FM and D-dimer in DIC

                                                Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                Non Overt DIC Overt DIC

                                                AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                Trends in Markers of DIC for Different Patients

                                                Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                Trends in Markers of DIC for Different Patients

                                                Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                28 day outcome survival

                                                28 day outcome death

                                                Determination of Cutoffs of FM and D-dimer in DIC

                                                Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                Determination of Cutoffs of FM and D-dimer in DIC

                                                Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                DIC Case Studies

                                                Case Study 1 - Presentation

                                                18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                WBC count 77 KμL 423 ndash 907 x KμL

                                                RBC count 17 MμL 137 ndash 175 x MμL

                                                Hemoglobin 67 gdL 137 ndash 175 gdL

                                                Hematocrit 195 401 ndash 510

                                                MCV 95 fL 790 ndash 922 fL

                                                MPV 12 fL 94 ndash 124 fL

                                                Platelet count 9 KμL 161 ndash 347 KμL

                                                Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                Lymphocytes monocytes eosinophils basophils all below normal range

                                                PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                Case Study 1 ndash Microscopy

                                                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                DIC due to TF release by APL blasts

                                                Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                Case Study 2 ndash Presentation

                                                TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                PT 30 sec 113 ndash 146 sec

                                                APTT 75 sec 25 ndash 34 sec

                                                D-dimer 078 microgml FEU lt050 microgml FEU

                                                Fibrinogen 92 mgdl 150-400 mgdl

                                                pH 728 738 to 742

                                                PaO2 570 mmHg 80-100 mmHg

                                                WBC 33 times 103mm3 40-11 times 103mm3

                                                ALT 111 IUL 0ndash34 IUL

                                                AST 61 IUL 0ndash34 IUL

                                                BUN 303 mgdL 08-13 mgdL

                                                Case Study 2 ndash Lab Results

                                                Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                Case Study 2 ndash Diagnosis

                                                60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                Case Study 3 ndash Presentation

                                                TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                PT 228 sec 113 ndash 146 sec

                                                APTT 45 sec 25 ndash 34 sec

                                                D-dimer 080 microgml FEU lt050 microgmL FEU

                                                Fibrinogen 82 mgdL 150-400 mgdL

                                                FV Normal 70-120

                                                FVII Normal 55-170

                                                FVIII Normal 60-150

                                                Protein C Normal 70-130

                                                Hb 134 gdL 14-16 gdL

                                                WBC 81 times 103mm3 40-11 times 103mm3

                                                ALT 32 IUL 0ndash34 IUL

                                                AST 28 IUL 0ndash34 IUL

                                                BUN 09 mgdL 08-13 mgdL

                                                Case Study 3 ndash Lab Results

                                                Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                Case Study 3 ndash Diagnosis and Therapy

                                                Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                Case Study 4 ndash Presentation

                                                TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                PT 28 sec 113 ndash 146 sec

                                                APTT 71 sec 25 ndash 34 sec

                                                D-dimer 31 microgmL FEU lt050 microgml FEU

                                                Fibrinogen 92 mgdL 150-400 mgdl

                                                FV Normal 70-120

                                                FVII Normal 55-170

                                                FVIII Normal 60-150

                                                Protein C Normal 70-130

                                                Hb 158 gdL 14-16 gdL

                                                WBC 71 times 103mm3 40-11 times 103mm3

                                                ALT 60 IUL 0ndash34 IUL

                                                AST 47 IUL 0ndash34 IUL

                                                BUN 38 mgdL 08-13 mgdL

                                                Case Study 4 ndash Lab Results

                                                Lyme disease with DICProvide antibiotics with supportive measures

                                                Case Study 4 ndash Diagnosis

                                                55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                Case Study 5 ndash Presentation

                                                Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                Case Study 5 ndash Lab Results and Time Course

                                                Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                TEST RESULT REFERENCE RANGE

                                                Platelet count 33 x 109L 150-450 x 109L

                                                PT 215 sec 103 ndash 128 sec

                                                APTT 44 sec 26 ndash 36 sec

                                                D-dimer 20 microgmL FEU lt025 microgml FEU

                                                Fibrinogen 34 mgdL 200-375 mgdl

                                                FII FV FVIII Low Not reported (NR)

                                                FVII FIX FX vWF Normal NR

                                                Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                (D) Illustration demonstrating repair

                                                Case Study 5 ndash Diagnosis and Treatment

                                                Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                Case Study 6 ndash Presentation

                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                Case Study 6 ndash Lab Results

                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                PT 63 sec gt control 113 ndash 146 sec

                                                INR 658 1 ndash 125

                                                APTT 80 sec gt control 25 ndash 34 sec

                                                D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                Urine exam Proteinuria and hematuria 150-400 mgdl

                                                Albumin 28 gdL NR

                                                Hb 58 gdL NR

                                                LDH 1196 UL NR

                                                SGPT 144 IU NR

                                                SGOT 88 IU NR

                                                Bilirubin 32 mgdL NR

                                                DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                day postop

                                                Case Study 6 ndash Diagnosis and Treatment

                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                Case Study 6 ndash Discussion

                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                Case Study 7 ndash Presentation

                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                Case Study 7 ndash Presentation

                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                Case Study 7 ndash Lab Results vs Time

                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                Case Study 7 ndash Diagnosis and Treatment

                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                Case Study 7 ndash Diagnosis and Treatment

                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                DIC Take Home Messages

                                                Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                DIC

                                                Thank you Questions

                                                • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                • Learning Objectives
                                                • Slide Number 3
                                                • Slide Number 4
                                                • Slide Number 5
                                                • Slide Number 6
                                                • Slide Number 7
                                                • Slide Number 8
                                                • Wound Sealing
                                                • The Three Steps of Hemostasis
                                                • Vessel Wall
                                                • Slide Number 12
                                                • Slide Number 13
                                                • Platelet Structure UnactivatedActivated
                                                • Primary Hemostasis
                                                • Primary Hemostasis Assays
                                                • Slide Number 17
                                                • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                • Slide Number 19
                                                • Coagulation factors
                                                • Coagulation Assay Mechanisms
                                                • Slide Number 22
                                                • Fibrin Formation
                                                • Slide Number 24
                                                • Fibrinolysis Overview
                                                • Fibrinolysis Overview
                                                • Slide Number 27
                                                • Fibrinolysis Releases D-dimers
                                                • Basic Pathophysiology of DIC
                                                • Disseminated Intravascular Coagulation (DIC)
                                                • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                • Clinical Conditions Associated With DIC
                                                • Frequency of DIC in Selected Disease States
                                                • Underlying Diseases in DIC Patients
                                                • Slide Number 36
                                                • Slide Number 37
                                                • Slide Number 38
                                                • Slide Number 39
                                                • Pathophysiology of DIC
                                                • Pathogenesis of DIC in Sepsis
                                                • Host Response in Severe Sepsis
                                                • Organ Failure in Severe Sepsis
                                                • Mechanism of DIC in Organ Failure
                                                • Interaction of Inflammation and Coagulation in Sepsis
                                                • Slide Number 47
                                                • Diverse and Opposing Effects of Thrombin
                                                • Coagulation and Fibrinolysis in DIC
                                                • Mechanism of DIC
                                                • Pathophysiology of DIC
                                                • Pathophysiology of DIC - Mechanism
                                                • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                • Sub-Acute and Non-Overt DIC Clinical Findings
                                                • Pathophysiology of Overt DIC
                                                • Physiopathology of DIC ndash Overt DIC Findings
                                                • Slide Number 57
                                                • Slide Number 58
                                                • Slide Number 59
                                                • Slide Number 60
                                                • Slide Number 61
                                                • BREAK
                                                • Diagnostic and Management Approach for DIC
                                                • Diagnosis of DIC
                                                • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                • Lab Diagnosis of DIC ndash Screening Tests
                                                • Slide Number 67
                                                • Slide Number 68
                                                • British Journal of Haematology Overt DIC Score
                                                • Slide Number 70
                                                • Slide Number 71
                                                • Slide Number 72
                                                • Slide Number 73
                                                • DIC Management Goals
                                                • DIC Management and Treatment
                                                • DIC Management Strategies
                                                • Anticoagulant Factor Concentrate Treatment
                                                • Anticoagulant Factor Concentrate Treatment Trials
                                                • Markers of Thrombin amp Plasmin Generation in DIC
                                                • D-dimer FDPs and DIC
                                                • D-Dimer and FDPs in DIC
                                                • Follow Up of DIC State of Disease
                                                • FMD-Dimer in DIC Major Differences
                                                • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                • Slide Number 85
                                                • Slide Number 86
                                                • Comparing an Automated FM vs Manual FSP Test
                                                • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                • Slide Number 94
                                                • Slide Number 95
                                                • Slide Number 96
                                                • Slide Number 97
                                                • Slide Number 98
                                                • Slide Number 99
                                                • DIC Case Studies
                                                • Case Study 1 - Presentation
                                                • Case Study 1 ndash Lab Results
                                                • Case Study 1 ndash Microscopy
                                                • Case Study 1 ndash Diagnosis and Therapy
                                                • Slide Number 105
                                                • Slide Number 106
                                                • Slide Number 107
                                                • Slide Number 108
                                                • Slide Number 109
                                                • Slide Number 110
                                                • Slide Number 111
                                                • Slide Number 112
                                                • Slide Number 113
                                                • Slide Number 114
                                                • Slide Number 115
                                                • Slide Number 116
                                                • Slide Number 117
                                                • Slide Number 118
                                                • Slide Number 119
                                                • Slide Number 120
                                                • Slide Number 121
                                                • Slide Number 122
                                                • Slide Number 123
                                                • Slide Number 124
                                                • Slide Number 125
                                                • DIC Take Home Messages
                                                • Slide Number 127
                                                • Slide Number 128

                                                  Fibrinolysis Overview

                                                  Destroys fibrin fibers

                                                  Destroys the scab (dried wound)

                                                  Maintains vessel integrity

                                                  Fibrinolysis Overview

                                                  Fibrin =cement fibers

                                                  Plasmin

                                                  Plasmin digests fibrin

                                                  t-PA

                                                  Pro Urokinase

                                                  Urokinase

                                                  PAI-1PAI-1

                                                  Plasminogen Plasmin

                                                  1st Step

                                                  2nd Step

                                                  Fibrinolysis Cascade

                                                  t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin

                                                  Extrinsic pathway(endothelia l cells)

                                                  Intrinsic pathway(plasma)

                                                  Fibrin clot

                                                  D-dimerFibrin degradation products

                                                  Fibrin

                                                  TAFIa

                                                  APAntiplasmin(amp a2-MG)

                                                  PK Kallikrein

                                                  XII

                                                  Fibrinolysis Releases D-dimers

                                                  D-dimer presence fibrin has been formed and digested in patients body

                                                  Normal D-dimer level no thrombosis occurred in the patient

                                                  Basic Pathophysiology of DIC

                                                  Disseminated Intravascular Coagulation (DIC)

                                                  Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management

                                                  Clinical Manifestations of DICOrgan Ischemic Hemorrhagic

                                                  Skin Pupura Fulminans Petechiae

                                                  Gangrene Echymoses

                                                  Acral cyanosis Oozing

                                                  CNS Deliriumcoma Intracranial

                                                  Infarcts Bleeding

                                                  Renal OliguriaAzotemia Hematuria

                                                  Cortical Necrosis

                                                  Cardiovascular Myocardial dysfunction

                                                  Pulmonary DyspneaHypoxia Hemorrhagic lung

                                                  Infarct

                                                  Gastrointestinal Ulcers infarcts Massive hemorrhage

                                                  Endocrine Adrenal infarcts

                                                  Purpura Fulminans with DIC Due to Meningococcal Sepsis

                                                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                  Clinical Conditions Associated With DIC

                                                  Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                  Frequency of DIC in Selected Disease States

                                                  Disease Frequency

                                                  Gram-negative sepsis 30-50

                                                  Severe trauma and systemic inflammation 50-70

                                                  Metastasized tumors 15

                                                  Abruptio placentaamniotic fluid embolism 50

                                                  Severe preeclampsia 7

                                                  Giant hemangioma 25

                                                  Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                                  Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017

                                                  Underlying Diseases in DIC Patients

                                                  In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively

                                                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                  Epidemiology of DIC

                                                  Impact of DIC Status on Mortality - 1

                                                  Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8

                                                  Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC

                                                  Impact of DIC Status on Mortality - 2

                                                  Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                                  Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients

                                                  Impact of Age on Mortality in DIC Patients

                                                  Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                                  Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)

                                                  Pathophysiology of DIC

                                                  Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                  Pathogenesis of DIC in Sepsis

                                                  Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15

                                                  Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC

                                                  Host Response in Severe Sepsis

                                                  Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral

                                                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                  Organ Failure in Severe Sepsis

                                                  Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure

                                                  Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51

                                                  Mechanism of DIC in Organ Failure

                                                  Underlying condition(sepsis trauma)

                                                  Cytokines

                                                  TF-mediatedactivation of coagulation

                                                  Depression of inhibitory systems

                                                  Reducesfibrinolysis

                                                  Fibrin deposition

                                                  Organ failure

                                                  Inadequate fibrin removal

                                                  Fibrinformation

                                                  Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )

                                                  Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705

                                                  Interaction of Inflammation and Coagulation in Sepsis

                                                  Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines

                                                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                  Mechanism of Multiple Organ Failure in DIC

                                                  Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

                                                  Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

                                                  lipopolysaccharides

                                                  cytokines

                                                  coagulation activation

                                                  mononuclear cell

                                                  tissue factor

                                                  Diverse and Opposing Effects of Thrombin

                                                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                  Coagulation and Fibrinolysis in DIC

                                                  Soluble fibrin Polymer

                                                  XIIIa

                                                  D-Dimer

                                                  E

                                                  Fibrin clot

                                                  Fibrin Degradation Products

                                                  Fibrinogen Thrombin

                                                  Fibrinogen Degradation

                                                  Products

                                                  D E

                                                  Plasmin

                                                  DFM + fibrinopeptides

                                                  Soluble FM ComplexesPre-throm

                                                  boticPost-throm

                                                  botic

                                                  Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

                                                  Mechanism of DIC

                                                  THROMBOSIS

                                                  Fibrin

                                                  Blood activationEndothelial lysisTF expression

                                                  BLEEDING

                                                  FDPs

                                                  D-Dimer

                                                  Plasmin

                                                  Pathophysiology of DIC

                                                  1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

                                                  thromboplastin influx of activated cells (monocytes macrophages)

                                                  Results in an intravascular deposition of fibrin

                                                  Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

                                                  Second step Consumption and depletion of coagulation factors inhibitors (Protein C

                                                  Protein S AT) and platelets Local fibrinolytic response

                                                  bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

                                                  FDP and D-Dimer

                                                  Bleeding

                                                  Pathophysiology of DIC - Mechanism

                                                  Systemic activation of coagulation

                                                  Intravasculardepositionof fibrin

                                                  Thrombosis of small and midsize vessels

                                                  and organ failure

                                                  Depletion of platelets and

                                                  coagulation factors

                                                  Bleeding

                                                  Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                                  Pathophysiology of DIC ndash 2 Types of Clinical pictures

                                                  Chronic = non - overt DICMay be unrecognized clinically

                                                  Acute = overt DIClife threatening bleedingor multiple organ failure

                                                  Sub-Acute and Non-Overt DIC Clinical Findings

                                                  Compensated non-overt DIC Steady low level or intermittent activation

                                                  bull Compensated by increased production of coagulation components and platelets

                                                  Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                                                  Risk of decompensation leading to overt DIC

                                                  Pathophysiology of Overt DIC

                                                  Massive activation of coagulation and fibrinolysis

                                                  Does not allow for compensatory efforts

                                                  Rapid depletion of coagulation factors inhibitors and platelets

                                                  Thrombosis multiple organ failures

                                                  Bleeding complications and shock

                                                  Physiopathology of DIC ndash Overt DIC Findings

                                                  Thrombin generation

                                                  Thrombosis

                                                  Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                                                  Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                                                  Plasmin generationHemorrhage

                                                  bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                                                  bull Tachycardia hypotension edema

                                                  Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                  Pathogenesis Pathways in DIC

                                                  Cytokines

                                                  TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                                                  fibrin inadequateformation fibrin removal

                                                  Fibrin deposition

                                                  Inflammation

                                                  Coagulation

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                                                  wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

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                                                  HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

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                                                  BREAK

                                                  Diagnostic and Management Approach for DIC

                                                  Diagnosis of DIC

                                                  Clinical diagnosis is obvious in cases of overt DIC

                                                  Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                                  Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                                  Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                                  Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                                  Important to recognize simultaneous formation of thrombin and plasmin

                                                  Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                  Lab Diagnosis of DIC ndash Screening Tests

                                                  Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                  Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                                  fibrinogen level) repeat testing assesses progression

                                                  Screening tests not clinically specific or sensitive for DIC

                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                  Laboratory Changes in Overt DIC

                                                  DIC Diagnostic Practices Over Time

                                                  Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                  British Journal of Haematology Overt DIC Score

                                                  Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                  ISTH Step by Step DIC Algorithm

                                                  Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                  US Based Validation of ISTH DIC Score

                                                  When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                  Differential Diagnosis in DIC

                                                  aHUS atypical hemolytic uremic syndrome

                                                  HUS hemolytic uremic syndrome

                                                  HIT heparin-induced thrombocytopenia

                                                  ITP immune thrombocytopenic purpura

                                                  TTP thrombotic thrombocytopenic purpura

                                                  DIC and MAHA

                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                  lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                  When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                  DIC Management Goals

                                                  Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                  Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                  DIC Management and Treatment

                                                  Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                  Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                  requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                  Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                  DIC Management Strategies

                                                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                  Anticoagulant Factor Concentrate Treatment

                                                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                  Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                  Anticoagulant Factor Concentrate Treatment Trials

                                                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                  Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                  Markers of Thrombin amp Plasmin Generation in DIC

                                                  D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                  Cut-off value

                                                  Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                  degradation products Sensitive assay typically with cutoff adapted for DIC

                                                  D-dimer FDPs and DIC

                                                  D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                  Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                  Follow Up of DIC State of Disease

                                                  Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                  Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                  FMD-Dimer in DIC Major Differences

                                                  onset of thrombosis

                                                  days

                                                  Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                  FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                  D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                  of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                  0

                                                  20

                                                  40

                                                  60

                                                  80

                                                  100

                                                  94 85 90N = 62

                                                  Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                  Positivity of Test Results ISTH Score and Disease State

                                                  Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                  Red bar positive for 2 points of DIC score

                                                  Pink bar positive for 1-2 points of DIC score

                                                  HT hematopoietic tumor

                                                  IF infection

                                                  SC solid cancer

                                                  Markers in Patients with or without DIC

                                                  Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                  HT hematopoietic tumorIF infectionSC solid cancer

                                                  Comparing an Automated FM vs Manual FSP Test

                                                  Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                  Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                  Automated (Mitsubishi) vs Automated (Stago)

                                                  In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                  Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                  In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                  In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                  In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                  Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                  No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                  Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                  Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                  Non Overt DIC Overt DIC

                                                  AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                  Trends in Markers of DIC for Different Patients

                                                  Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                  Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                  Trends in Markers of DIC for Different Patients

                                                  Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                  FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                  28 day outcome survival

                                                  28 day outcome death

                                                  Determination of Cutoffs of FM and D-dimer in DIC

                                                  Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                  Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                  Determination of Cutoffs of FM and D-dimer in DIC

                                                  Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                  Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                  DIC Case Studies

                                                  Case Study 1 - Presentation

                                                  18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                  Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                  WBC count 77 KμL 423 ndash 907 x KμL

                                                  RBC count 17 MμL 137 ndash 175 x MμL

                                                  Hemoglobin 67 gdL 137 ndash 175 gdL

                                                  Hematocrit 195 401 ndash 510

                                                  MCV 95 fL 790 ndash 922 fL

                                                  MPV 12 fL 94 ndash 124 fL

                                                  Platelet count 9 KμL 161 ndash 347 KμL

                                                  Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                  Lymphocytes monocytes eosinophils basophils all below normal range

                                                  PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                  APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                  Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                  D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                  Case Study 1 ndash Microscopy

                                                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                  Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                  Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                  DIC due to TF release by APL blasts

                                                  Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                  Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                  20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                  Case Study 2 ndash Presentation

                                                  TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                  PT 30 sec 113 ndash 146 sec

                                                  APTT 75 sec 25 ndash 34 sec

                                                  D-dimer 078 microgml FEU lt050 microgml FEU

                                                  Fibrinogen 92 mgdl 150-400 mgdl

                                                  pH 728 738 to 742

                                                  PaO2 570 mmHg 80-100 mmHg

                                                  WBC 33 times 103mm3 40-11 times 103mm3

                                                  ALT 111 IUL 0ndash34 IUL

                                                  AST 61 IUL 0ndash34 IUL

                                                  BUN 303 mgdL 08-13 mgdL

                                                  Case Study 2 ndash Lab Results

                                                  Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                  Case Study 2 ndash Diagnosis

                                                  60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                  Case Study 3 ndash Presentation

                                                  TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                  PT 228 sec 113 ndash 146 sec

                                                  APTT 45 sec 25 ndash 34 sec

                                                  D-dimer 080 microgml FEU lt050 microgmL FEU

                                                  Fibrinogen 82 mgdL 150-400 mgdL

                                                  FV Normal 70-120

                                                  FVII Normal 55-170

                                                  FVIII Normal 60-150

                                                  Protein C Normal 70-130

                                                  Hb 134 gdL 14-16 gdL

                                                  WBC 81 times 103mm3 40-11 times 103mm3

                                                  ALT 32 IUL 0ndash34 IUL

                                                  AST 28 IUL 0ndash34 IUL

                                                  BUN 09 mgdL 08-13 mgdL

                                                  Case Study 3 ndash Lab Results

                                                  Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                  Case Study 3 ndash Diagnosis and Therapy

                                                  Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                  Case Study 4 ndash Presentation

                                                  TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                  PT 28 sec 113 ndash 146 sec

                                                  APTT 71 sec 25 ndash 34 sec

                                                  D-dimer 31 microgmL FEU lt050 microgml FEU

                                                  Fibrinogen 92 mgdL 150-400 mgdl

                                                  FV Normal 70-120

                                                  FVII Normal 55-170

                                                  FVIII Normal 60-150

                                                  Protein C Normal 70-130

                                                  Hb 158 gdL 14-16 gdL

                                                  WBC 71 times 103mm3 40-11 times 103mm3

                                                  ALT 60 IUL 0ndash34 IUL

                                                  AST 47 IUL 0ndash34 IUL

                                                  BUN 38 mgdL 08-13 mgdL

                                                  Case Study 4 ndash Lab Results

                                                  Lyme disease with DICProvide antibiotics with supportive measures

                                                  Case Study 4 ndash Diagnosis

                                                  55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                  Case Study 5 ndash Presentation

                                                  Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                  Case Study 5 ndash Lab Results and Time Course

                                                  Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                  TEST RESULT REFERENCE RANGE

                                                  Platelet count 33 x 109L 150-450 x 109L

                                                  PT 215 sec 103 ndash 128 sec

                                                  APTT 44 sec 26 ndash 36 sec

                                                  D-dimer 20 microgmL FEU lt025 microgml FEU

                                                  Fibrinogen 34 mgdL 200-375 mgdl

                                                  FII FV FVIII Low Not reported (NR)

                                                  FVII FIX FX vWF Normal NR

                                                  Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                  DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                  dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                  (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                  (D) Illustration demonstrating repair

                                                  Case Study 5 ndash Diagnosis and Treatment

                                                  Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                  29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                  Case Study 6 ndash Presentation

                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                  Case Study 6 ndash Lab Results

                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                  TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                  PT 63 sec gt control 113 ndash 146 sec

                                                  INR 658 1 ndash 125

                                                  APTT 80 sec gt control 25 ndash 34 sec

                                                  D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                  Urine exam Proteinuria and hematuria 150-400 mgdl

                                                  Albumin 28 gdL NR

                                                  Hb 58 gdL NR

                                                  LDH 1196 UL NR

                                                  SGPT 144 IU NR

                                                  SGOT 88 IU NR

                                                  Bilirubin 32 mgdL NR

                                                  DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                  day postop

                                                  Case Study 6 ndash Diagnosis and Treatment

                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                  HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                  Case Study 6 ndash Discussion

                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                  44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                  Case Study 7 ndash Presentation

                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                  On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                  Case Study 7 ndash Presentation

                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                  Case Study 7 ndash Lab Results vs Time

                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                  Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                  Case Study 7 ndash Diagnosis and Treatment

                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                  On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                  Case Study 7 ndash Diagnosis and Treatment

                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                  DIC Take Home Messages

                                                  Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                  Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                  DIC

                                                  Thank you Questions

                                                  • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                  • Learning Objectives
                                                  • Slide Number 3
                                                  • Slide Number 4
                                                  • Slide Number 5
                                                  • Slide Number 6
                                                  • Slide Number 7
                                                  • Slide Number 8
                                                  • Wound Sealing
                                                  • The Three Steps of Hemostasis
                                                  • Vessel Wall
                                                  • Slide Number 12
                                                  • Slide Number 13
                                                  • Platelet Structure UnactivatedActivated
                                                  • Primary Hemostasis
                                                  • Primary Hemostasis Assays
                                                  • Slide Number 17
                                                  • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                  • Slide Number 19
                                                  • Coagulation factors
                                                  • Coagulation Assay Mechanisms
                                                  • Slide Number 22
                                                  • Fibrin Formation
                                                  • Slide Number 24
                                                  • Fibrinolysis Overview
                                                  • Fibrinolysis Overview
                                                  • Slide Number 27
                                                  • Fibrinolysis Releases D-dimers
                                                  • Basic Pathophysiology of DIC
                                                  • Disseminated Intravascular Coagulation (DIC)
                                                  • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                  • Clinical Conditions Associated With DIC
                                                  • Frequency of DIC in Selected Disease States
                                                  • Underlying Diseases in DIC Patients
                                                  • Slide Number 36
                                                  • Slide Number 37
                                                  • Slide Number 38
                                                  • Slide Number 39
                                                  • Pathophysiology of DIC
                                                  • Pathogenesis of DIC in Sepsis
                                                  • Host Response in Severe Sepsis
                                                  • Organ Failure in Severe Sepsis
                                                  • Mechanism of DIC in Organ Failure
                                                  • Interaction of Inflammation and Coagulation in Sepsis
                                                  • Slide Number 47
                                                  • Diverse and Opposing Effects of Thrombin
                                                  • Coagulation and Fibrinolysis in DIC
                                                  • Mechanism of DIC
                                                  • Pathophysiology of DIC
                                                  • Pathophysiology of DIC - Mechanism
                                                  • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                  • Sub-Acute and Non-Overt DIC Clinical Findings
                                                  • Pathophysiology of Overt DIC
                                                  • Physiopathology of DIC ndash Overt DIC Findings
                                                  • Slide Number 57
                                                  • Slide Number 58
                                                  • Slide Number 59
                                                  • Slide Number 60
                                                  • Slide Number 61
                                                  • BREAK
                                                  • Diagnostic and Management Approach for DIC
                                                  • Diagnosis of DIC
                                                  • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                  • Lab Diagnosis of DIC ndash Screening Tests
                                                  • Slide Number 67
                                                  • Slide Number 68
                                                  • British Journal of Haematology Overt DIC Score
                                                  • Slide Number 70
                                                  • Slide Number 71
                                                  • Slide Number 72
                                                  • Slide Number 73
                                                  • DIC Management Goals
                                                  • DIC Management and Treatment
                                                  • DIC Management Strategies
                                                  • Anticoagulant Factor Concentrate Treatment
                                                  • Anticoagulant Factor Concentrate Treatment Trials
                                                  • Markers of Thrombin amp Plasmin Generation in DIC
                                                  • D-dimer FDPs and DIC
                                                  • D-Dimer and FDPs in DIC
                                                  • Follow Up of DIC State of Disease
                                                  • FMD-Dimer in DIC Major Differences
                                                  • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                  • Slide Number 85
                                                  • Slide Number 86
                                                  • Comparing an Automated FM vs Manual FSP Test
                                                  • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                  • Slide Number 94
                                                  • Slide Number 95
                                                  • Slide Number 96
                                                  • Slide Number 97
                                                  • Slide Number 98
                                                  • Slide Number 99
                                                  • DIC Case Studies
                                                  • Case Study 1 - Presentation
                                                  • Case Study 1 ndash Lab Results
                                                  • Case Study 1 ndash Microscopy
                                                  • Case Study 1 ndash Diagnosis and Therapy
                                                  • Slide Number 105
                                                  • Slide Number 106
                                                  • Slide Number 107
                                                  • Slide Number 108
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                                                  • Slide Number 125
                                                  • DIC Take Home Messages
                                                  • Slide Number 127
                                                  • Slide Number 128

                                                    Fibrinolysis Overview

                                                    Fibrin =cement fibers

                                                    Plasmin

                                                    Plasmin digests fibrin

                                                    t-PA

                                                    Pro Urokinase

                                                    Urokinase

                                                    PAI-1PAI-1

                                                    Plasminogen Plasmin

                                                    1st Step

                                                    2nd Step

                                                    Fibrinolysis Cascade

                                                    t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin

                                                    Extrinsic pathway(endothelia l cells)

                                                    Intrinsic pathway(plasma)

                                                    Fibrin clot

                                                    D-dimerFibrin degradation products

                                                    Fibrin

                                                    TAFIa

                                                    APAntiplasmin(amp a2-MG)

                                                    PK Kallikrein

                                                    XII

                                                    Fibrinolysis Releases D-dimers

                                                    D-dimer presence fibrin has been formed and digested in patients body

                                                    Normal D-dimer level no thrombosis occurred in the patient

                                                    Basic Pathophysiology of DIC

                                                    Disseminated Intravascular Coagulation (DIC)

                                                    Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management

                                                    Clinical Manifestations of DICOrgan Ischemic Hemorrhagic

                                                    Skin Pupura Fulminans Petechiae

                                                    Gangrene Echymoses

                                                    Acral cyanosis Oozing

                                                    CNS Deliriumcoma Intracranial

                                                    Infarcts Bleeding

                                                    Renal OliguriaAzotemia Hematuria

                                                    Cortical Necrosis

                                                    Cardiovascular Myocardial dysfunction

                                                    Pulmonary DyspneaHypoxia Hemorrhagic lung

                                                    Infarct

                                                    Gastrointestinal Ulcers infarcts Massive hemorrhage

                                                    Endocrine Adrenal infarcts

                                                    Purpura Fulminans with DIC Due to Meningococcal Sepsis

                                                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                    Clinical Conditions Associated With DIC

                                                    Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                    Frequency of DIC in Selected Disease States

                                                    Disease Frequency

                                                    Gram-negative sepsis 30-50

                                                    Severe trauma and systemic inflammation 50-70

                                                    Metastasized tumors 15

                                                    Abruptio placentaamniotic fluid embolism 50

                                                    Severe preeclampsia 7

                                                    Giant hemangioma 25

                                                    Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                                    Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017

                                                    Underlying Diseases in DIC Patients

                                                    In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively

                                                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                    Epidemiology of DIC

                                                    Impact of DIC Status on Mortality - 1

                                                    Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8

                                                    Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC

                                                    Impact of DIC Status on Mortality - 2

                                                    Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                                    Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients

                                                    Impact of Age on Mortality in DIC Patients

                                                    Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                                    Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)

                                                    Pathophysiology of DIC

                                                    Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                    Pathogenesis of DIC in Sepsis

                                                    Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15

                                                    Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC

                                                    Host Response in Severe Sepsis

                                                    Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral

                                                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                    Organ Failure in Severe Sepsis

                                                    Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure

                                                    Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51

                                                    Mechanism of DIC in Organ Failure

                                                    Underlying condition(sepsis trauma)

                                                    Cytokines

                                                    TF-mediatedactivation of coagulation

                                                    Depression of inhibitory systems

                                                    Reducesfibrinolysis

                                                    Fibrin deposition

                                                    Organ failure

                                                    Inadequate fibrin removal

                                                    Fibrinformation

                                                    Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )

                                                    Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705

                                                    Interaction of Inflammation and Coagulation in Sepsis

                                                    Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines

                                                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                    Mechanism of Multiple Organ Failure in DIC

                                                    Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

                                                    Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

                                                    lipopolysaccharides

                                                    cytokines

                                                    coagulation activation

                                                    mononuclear cell

                                                    tissue factor

                                                    Diverse and Opposing Effects of Thrombin

                                                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                    Coagulation and Fibrinolysis in DIC

                                                    Soluble fibrin Polymer

                                                    XIIIa

                                                    D-Dimer

                                                    E

                                                    Fibrin clot

                                                    Fibrin Degradation Products

                                                    Fibrinogen Thrombin

                                                    Fibrinogen Degradation

                                                    Products

                                                    D E

                                                    Plasmin

                                                    DFM + fibrinopeptides

                                                    Soluble FM ComplexesPre-throm

                                                    boticPost-throm

                                                    botic

                                                    Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

                                                    Mechanism of DIC

                                                    THROMBOSIS

                                                    Fibrin

                                                    Blood activationEndothelial lysisTF expression

                                                    BLEEDING

                                                    FDPs

                                                    D-Dimer

                                                    Plasmin

                                                    Pathophysiology of DIC

                                                    1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

                                                    thromboplastin influx of activated cells (monocytes macrophages)

                                                    Results in an intravascular deposition of fibrin

                                                    Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

                                                    Second step Consumption and depletion of coagulation factors inhibitors (Protein C

                                                    Protein S AT) and platelets Local fibrinolytic response

                                                    bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

                                                    FDP and D-Dimer

                                                    Bleeding

                                                    Pathophysiology of DIC - Mechanism

                                                    Systemic activation of coagulation

                                                    Intravasculardepositionof fibrin

                                                    Thrombosis of small and midsize vessels

                                                    and organ failure

                                                    Depletion of platelets and

                                                    coagulation factors

                                                    Bleeding

                                                    Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                                    Pathophysiology of DIC ndash 2 Types of Clinical pictures

                                                    Chronic = non - overt DICMay be unrecognized clinically

                                                    Acute = overt DIClife threatening bleedingor multiple organ failure

                                                    Sub-Acute and Non-Overt DIC Clinical Findings

                                                    Compensated non-overt DIC Steady low level or intermittent activation

                                                    bull Compensated by increased production of coagulation components and platelets

                                                    Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                                                    Risk of decompensation leading to overt DIC

                                                    Pathophysiology of Overt DIC

                                                    Massive activation of coagulation and fibrinolysis

                                                    Does not allow for compensatory efforts

                                                    Rapid depletion of coagulation factors inhibitors and platelets

                                                    Thrombosis multiple organ failures

                                                    Bleeding complications and shock

                                                    Physiopathology of DIC ndash Overt DIC Findings

                                                    Thrombin generation

                                                    Thrombosis

                                                    Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                                                    Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                                                    Plasmin generationHemorrhage

                                                    bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                                                    bull Tachycardia hypotension edema

                                                    Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                    Pathogenesis Pathways in DIC

                                                    Cytokines

                                                    TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                                                    fibrin inadequateformation fibrin removal

                                                    Fibrin deposition

                                                    Inflammation

                                                    Coagulation

                                                    Stago Celebrates Lab Week 2017

                                                    NA

                                                    Stago 247 Educational Webinar Sites

                                                    wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                                                    wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                                                    Stago Educational Apps

                                                    HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                                                    iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                                                    BREAK

                                                    Diagnostic and Management Approach for DIC

                                                    Diagnosis of DIC

                                                    Clinical diagnosis is obvious in cases of overt DIC

                                                    Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                                    Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                                    Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                                    Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                                    Important to recognize simultaneous formation of thrombin and plasmin

                                                    Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                    Lab Diagnosis of DIC ndash Screening Tests

                                                    Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                    Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                                    fibrinogen level) repeat testing assesses progression

                                                    Screening tests not clinically specific or sensitive for DIC

                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                    Laboratory Changes in Overt DIC

                                                    DIC Diagnostic Practices Over Time

                                                    Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                    British Journal of Haematology Overt DIC Score

                                                    Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                    ISTH Step by Step DIC Algorithm

                                                    Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                    US Based Validation of ISTH DIC Score

                                                    When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                    Differential Diagnosis in DIC

                                                    aHUS atypical hemolytic uremic syndrome

                                                    HUS hemolytic uremic syndrome

                                                    HIT heparin-induced thrombocytopenia

                                                    ITP immune thrombocytopenic purpura

                                                    TTP thrombotic thrombocytopenic purpura

                                                    DIC and MAHA

                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                    lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                    When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                    DIC Management Goals

                                                    Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                    Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                    DIC Management and Treatment

                                                    Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                    Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                    requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                    Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                    DIC Management Strategies

                                                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                    Anticoagulant Factor Concentrate Treatment

                                                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                    Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                    Anticoagulant Factor Concentrate Treatment Trials

                                                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                    Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                    Markers of Thrombin amp Plasmin Generation in DIC

                                                    D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                    Cut-off value

                                                    Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                    degradation products Sensitive assay typically with cutoff adapted for DIC

                                                    D-dimer FDPs and DIC

                                                    D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                    Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                    Follow Up of DIC State of Disease

                                                    Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                    Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                    FMD-Dimer in DIC Major Differences

                                                    onset of thrombosis

                                                    days

                                                    Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                    FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                    D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                    of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                    0

                                                    20

                                                    40

                                                    60

                                                    80

                                                    100

                                                    94 85 90N = 62

                                                    Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                    Positivity of Test Results ISTH Score and Disease State

                                                    Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                    Red bar positive for 2 points of DIC score

                                                    Pink bar positive for 1-2 points of DIC score

                                                    HT hematopoietic tumor

                                                    IF infection

                                                    SC solid cancer

                                                    Markers in Patients with or without DIC

                                                    Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                    HT hematopoietic tumorIF infectionSC solid cancer

                                                    Comparing an Automated FM vs Manual FSP Test

                                                    Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                    Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                    Automated (Mitsubishi) vs Automated (Stago)

                                                    In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                    Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                    In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                    In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                    In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                    Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                    No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                    Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                    Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                    Non Overt DIC Overt DIC

                                                    AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                    Trends in Markers of DIC for Different Patients

                                                    Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                    Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                    Trends in Markers of DIC for Different Patients

                                                    Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                    FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                    28 day outcome survival

                                                    28 day outcome death

                                                    Determination of Cutoffs of FM and D-dimer in DIC

                                                    Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                    Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                    Determination of Cutoffs of FM and D-dimer in DIC

                                                    Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                    Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                    DIC Case Studies

                                                    Case Study 1 - Presentation

                                                    18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                    Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                    WBC count 77 KμL 423 ndash 907 x KμL

                                                    RBC count 17 MμL 137 ndash 175 x MμL

                                                    Hemoglobin 67 gdL 137 ndash 175 gdL

                                                    Hematocrit 195 401 ndash 510

                                                    MCV 95 fL 790 ndash 922 fL

                                                    MPV 12 fL 94 ndash 124 fL

                                                    Platelet count 9 KμL 161 ndash 347 KμL

                                                    Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                    Lymphocytes monocytes eosinophils basophils all below normal range

                                                    PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                    APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                    Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                    D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                    Case Study 1 ndash Microscopy

                                                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                    Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                    Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                    DIC due to TF release by APL blasts

                                                    Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                    Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                    20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                    Case Study 2 ndash Presentation

                                                    TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                    PT 30 sec 113 ndash 146 sec

                                                    APTT 75 sec 25 ndash 34 sec

                                                    D-dimer 078 microgml FEU lt050 microgml FEU

                                                    Fibrinogen 92 mgdl 150-400 mgdl

                                                    pH 728 738 to 742

                                                    PaO2 570 mmHg 80-100 mmHg

                                                    WBC 33 times 103mm3 40-11 times 103mm3

                                                    ALT 111 IUL 0ndash34 IUL

                                                    AST 61 IUL 0ndash34 IUL

                                                    BUN 303 mgdL 08-13 mgdL

                                                    Case Study 2 ndash Lab Results

                                                    Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                    Case Study 2 ndash Diagnosis

                                                    60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                    Case Study 3 ndash Presentation

                                                    TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                    PT 228 sec 113 ndash 146 sec

                                                    APTT 45 sec 25 ndash 34 sec

                                                    D-dimer 080 microgml FEU lt050 microgmL FEU

                                                    Fibrinogen 82 mgdL 150-400 mgdL

                                                    FV Normal 70-120

                                                    FVII Normal 55-170

                                                    FVIII Normal 60-150

                                                    Protein C Normal 70-130

                                                    Hb 134 gdL 14-16 gdL

                                                    WBC 81 times 103mm3 40-11 times 103mm3

                                                    ALT 32 IUL 0ndash34 IUL

                                                    AST 28 IUL 0ndash34 IUL

                                                    BUN 09 mgdL 08-13 mgdL

                                                    Case Study 3 ndash Lab Results

                                                    Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                    Case Study 3 ndash Diagnosis and Therapy

                                                    Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                    Case Study 4 ndash Presentation

                                                    TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                    PT 28 sec 113 ndash 146 sec

                                                    APTT 71 sec 25 ndash 34 sec

                                                    D-dimer 31 microgmL FEU lt050 microgml FEU

                                                    Fibrinogen 92 mgdL 150-400 mgdl

                                                    FV Normal 70-120

                                                    FVII Normal 55-170

                                                    FVIII Normal 60-150

                                                    Protein C Normal 70-130

                                                    Hb 158 gdL 14-16 gdL

                                                    WBC 71 times 103mm3 40-11 times 103mm3

                                                    ALT 60 IUL 0ndash34 IUL

                                                    AST 47 IUL 0ndash34 IUL

                                                    BUN 38 mgdL 08-13 mgdL

                                                    Case Study 4 ndash Lab Results

                                                    Lyme disease with DICProvide antibiotics with supportive measures

                                                    Case Study 4 ndash Diagnosis

                                                    55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                    Case Study 5 ndash Presentation

                                                    Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                    Case Study 5 ndash Lab Results and Time Course

                                                    Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                    TEST RESULT REFERENCE RANGE

                                                    Platelet count 33 x 109L 150-450 x 109L

                                                    PT 215 sec 103 ndash 128 sec

                                                    APTT 44 sec 26 ndash 36 sec

                                                    D-dimer 20 microgmL FEU lt025 microgml FEU

                                                    Fibrinogen 34 mgdL 200-375 mgdl

                                                    FII FV FVIII Low Not reported (NR)

                                                    FVII FIX FX vWF Normal NR

                                                    Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                    DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                    dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                    (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                    (D) Illustration demonstrating repair

                                                    Case Study 5 ndash Diagnosis and Treatment

                                                    Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                    29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                    Case Study 6 ndash Presentation

                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                    Case Study 6 ndash Lab Results

                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                    TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                    PT 63 sec gt control 113 ndash 146 sec

                                                    INR 658 1 ndash 125

                                                    APTT 80 sec gt control 25 ndash 34 sec

                                                    D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                    Urine exam Proteinuria and hematuria 150-400 mgdl

                                                    Albumin 28 gdL NR

                                                    Hb 58 gdL NR

                                                    LDH 1196 UL NR

                                                    SGPT 144 IU NR

                                                    SGOT 88 IU NR

                                                    Bilirubin 32 mgdL NR

                                                    DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                    day postop

                                                    Case Study 6 ndash Diagnosis and Treatment

                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                    HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                    Case Study 6 ndash Discussion

                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                    44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                    Case Study 7 ndash Presentation

                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                    On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                    Case Study 7 ndash Presentation

                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                    Case Study 7 ndash Lab Results vs Time

                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                    Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                    Case Study 7 ndash Diagnosis and Treatment

                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                    On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                    Case Study 7 ndash Diagnosis and Treatment

                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                    DIC Take Home Messages

                                                    Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                    Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                    DIC

                                                    Thank you Questions

                                                    • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                    • Learning Objectives
                                                    • Slide Number 3
                                                    • Slide Number 4
                                                    • Slide Number 5
                                                    • Slide Number 6
                                                    • Slide Number 7
                                                    • Slide Number 8
                                                    • Wound Sealing
                                                    • The Three Steps of Hemostasis
                                                    • Vessel Wall
                                                    • Slide Number 12
                                                    • Slide Number 13
                                                    • Platelet Structure UnactivatedActivated
                                                    • Primary Hemostasis
                                                    • Primary Hemostasis Assays
                                                    • Slide Number 17
                                                    • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                    • Slide Number 19
                                                    • Coagulation factors
                                                    • Coagulation Assay Mechanisms
                                                    • Slide Number 22
                                                    • Fibrin Formation
                                                    • Slide Number 24
                                                    • Fibrinolysis Overview
                                                    • Fibrinolysis Overview
                                                    • Slide Number 27
                                                    • Fibrinolysis Releases D-dimers
                                                    • Basic Pathophysiology of DIC
                                                    • Disseminated Intravascular Coagulation (DIC)
                                                    • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                    • Clinical Conditions Associated With DIC
                                                    • Frequency of DIC in Selected Disease States
                                                    • Underlying Diseases in DIC Patients
                                                    • Slide Number 36
                                                    • Slide Number 37
                                                    • Slide Number 38
                                                    • Slide Number 39
                                                    • Pathophysiology of DIC
                                                    • Pathogenesis of DIC in Sepsis
                                                    • Host Response in Severe Sepsis
                                                    • Organ Failure in Severe Sepsis
                                                    • Mechanism of DIC in Organ Failure
                                                    • Interaction of Inflammation and Coagulation in Sepsis
                                                    • Slide Number 47
                                                    • Diverse and Opposing Effects of Thrombin
                                                    • Coagulation and Fibrinolysis in DIC
                                                    • Mechanism of DIC
                                                    • Pathophysiology of DIC
                                                    • Pathophysiology of DIC - Mechanism
                                                    • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                    • Sub-Acute and Non-Overt DIC Clinical Findings
                                                    • Pathophysiology of Overt DIC
                                                    • Physiopathology of DIC ndash Overt DIC Findings
                                                    • Slide Number 57
                                                    • Slide Number 58
                                                    • Slide Number 59
                                                    • Slide Number 60
                                                    • Slide Number 61
                                                    • BREAK
                                                    • Diagnostic and Management Approach for DIC
                                                    • Diagnosis of DIC
                                                    • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                    • Lab Diagnosis of DIC ndash Screening Tests
                                                    • Slide Number 67
                                                    • Slide Number 68
                                                    • British Journal of Haematology Overt DIC Score
                                                    • Slide Number 70
                                                    • Slide Number 71
                                                    • Slide Number 72
                                                    • Slide Number 73
                                                    • DIC Management Goals
                                                    • DIC Management and Treatment
                                                    • DIC Management Strategies
                                                    • Anticoagulant Factor Concentrate Treatment
                                                    • Anticoagulant Factor Concentrate Treatment Trials
                                                    • Markers of Thrombin amp Plasmin Generation in DIC
                                                    • D-dimer FDPs and DIC
                                                    • D-Dimer and FDPs in DIC
                                                    • Follow Up of DIC State of Disease
                                                    • FMD-Dimer in DIC Major Differences
                                                    • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                    • Slide Number 85
                                                    • Slide Number 86
                                                    • Comparing an Automated FM vs Manual FSP Test
                                                    • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                    • Slide Number 94
                                                    • Slide Number 95
                                                    • Slide Number 96
                                                    • Slide Number 97
                                                    • Slide Number 98
                                                    • Slide Number 99
                                                    • DIC Case Studies
                                                    • Case Study 1 - Presentation
                                                    • Case Study 1 ndash Lab Results
                                                    • Case Study 1 ndash Microscopy
                                                    • Case Study 1 ndash Diagnosis and Therapy
                                                    • Slide Number 105
                                                    • Slide Number 106
                                                    • Slide Number 107
                                                    • Slide Number 108
                                                    • Slide Number 109
                                                    • Slide Number 110
                                                    • Slide Number 111
                                                    • Slide Number 112
                                                    • Slide Number 113
                                                    • Slide Number 114
                                                    • Slide Number 115
                                                    • Slide Number 116
                                                    • Slide Number 117
                                                    • Slide Number 118
                                                    • Slide Number 119
                                                    • Slide Number 120
                                                    • Slide Number 121
                                                    • Slide Number 122
                                                    • Slide Number 123
                                                    • Slide Number 124
                                                    • Slide Number 125
                                                    • DIC Take Home Messages
                                                    • Slide Number 127
                                                    • Slide Number 128

                                                      t-PA

                                                      Pro Urokinase

                                                      Urokinase

                                                      PAI-1PAI-1

                                                      Plasminogen Plasmin

                                                      1st Step

                                                      2nd Step

                                                      Fibrinolysis Cascade

                                                      t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin

                                                      Extrinsic pathway(endothelia l cells)

                                                      Intrinsic pathway(plasma)

                                                      Fibrin clot

                                                      D-dimerFibrin degradation products

                                                      Fibrin

                                                      TAFIa

                                                      APAntiplasmin(amp a2-MG)

                                                      PK Kallikrein

                                                      XII

                                                      Fibrinolysis Releases D-dimers

                                                      D-dimer presence fibrin has been formed and digested in patients body

                                                      Normal D-dimer level no thrombosis occurred in the patient

                                                      Basic Pathophysiology of DIC

                                                      Disseminated Intravascular Coagulation (DIC)

                                                      Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management

                                                      Clinical Manifestations of DICOrgan Ischemic Hemorrhagic

                                                      Skin Pupura Fulminans Petechiae

                                                      Gangrene Echymoses

                                                      Acral cyanosis Oozing

                                                      CNS Deliriumcoma Intracranial

                                                      Infarcts Bleeding

                                                      Renal OliguriaAzotemia Hematuria

                                                      Cortical Necrosis

                                                      Cardiovascular Myocardial dysfunction

                                                      Pulmonary DyspneaHypoxia Hemorrhagic lung

                                                      Infarct

                                                      Gastrointestinal Ulcers infarcts Massive hemorrhage

                                                      Endocrine Adrenal infarcts

                                                      Purpura Fulminans with DIC Due to Meningococcal Sepsis

                                                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                      Clinical Conditions Associated With DIC

                                                      Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                      Frequency of DIC in Selected Disease States

                                                      Disease Frequency

                                                      Gram-negative sepsis 30-50

                                                      Severe trauma and systemic inflammation 50-70

                                                      Metastasized tumors 15

                                                      Abruptio placentaamniotic fluid embolism 50

                                                      Severe preeclampsia 7

                                                      Giant hemangioma 25

                                                      Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                                      Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017

                                                      Underlying Diseases in DIC Patients

                                                      In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively

                                                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                      Epidemiology of DIC

                                                      Impact of DIC Status on Mortality - 1

                                                      Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8

                                                      Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC

                                                      Impact of DIC Status on Mortality - 2

                                                      Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                                      Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients

                                                      Impact of Age on Mortality in DIC Patients

                                                      Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                                      Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)

                                                      Pathophysiology of DIC

                                                      Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                      Pathogenesis of DIC in Sepsis

                                                      Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15

                                                      Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC

                                                      Host Response in Severe Sepsis

                                                      Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral

                                                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                      Organ Failure in Severe Sepsis

                                                      Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure

                                                      Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51

                                                      Mechanism of DIC in Organ Failure

                                                      Underlying condition(sepsis trauma)

                                                      Cytokines

                                                      TF-mediatedactivation of coagulation

                                                      Depression of inhibitory systems

                                                      Reducesfibrinolysis

                                                      Fibrin deposition

                                                      Organ failure

                                                      Inadequate fibrin removal

                                                      Fibrinformation

                                                      Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )

                                                      Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705

                                                      Interaction of Inflammation and Coagulation in Sepsis

                                                      Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines

                                                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                      Mechanism of Multiple Organ Failure in DIC

                                                      Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

                                                      Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

                                                      lipopolysaccharides

                                                      cytokines

                                                      coagulation activation

                                                      mononuclear cell

                                                      tissue factor

                                                      Diverse and Opposing Effects of Thrombin

                                                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                      Coagulation and Fibrinolysis in DIC

                                                      Soluble fibrin Polymer

                                                      XIIIa

                                                      D-Dimer

                                                      E

                                                      Fibrin clot

                                                      Fibrin Degradation Products

                                                      Fibrinogen Thrombin

                                                      Fibrinogen Degradation

                                                      Products

                                                      D E

                                                      Plasmin

                                                      DFM + fibrinopeptides

                                                      Soluble FM ComplexesPre-throm

                                                      boticPost-throm

                                                      botic

                                                      Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

                                                      Mechanism of DIC

                                                      THROMBOSIS

                                                      Fibrin

                                                      Blood activationEndothelial lysisTF expression

                                                      BLEEDING

                                                      FDPs

                                                      D-Dimer

                                                      Plasmin

                                                      Pathophysiology of DIC

                                                      1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

                                                      thromboplastin influx of activated cells (monocytes macrophages)

                                                      Results in an intravascular deposition of fibrin

                                                      Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

                                                      Second step Consumption and depletion of coagulation factors inhibitors (Protein C

                                                      Protein S AT) and platelets Local fibrinolytic response

                                                      bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

                                                      FDP and D-Dimer

                                                      Bleeding

                                                      Pathophysiology of DIC - Mechanism

                                                      Systemic activation of coagulation

                                                      Intravasculardepositionof fibrin

                                                      Thrombosis of small and midsize vessels

                                                      and organ failure

                                                      Depletion of platelets and

                                                      coagulation factors

                                                      Bleeding

                                                      Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                                      Pathophysiology of DIC ndash 2 Types of Clinical pictures

                                                      Chronic = non - overt DICMay be unrecognized clinically

                                                      Acute = overt DIClife threatening bleedingor multiple organ failure

                                                      Sub-Acute and Non-Overt DIC Clinical Findings

                                                      Compensated non-overt DIC Steady low level or intermittent activation

                                                      bull Compensated by increased production of coagulation components and platelets

                                                      Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                                                      Risk of decompensation leading to overt DIC

                                                      Pathophysiology of Overt DIC

                                                      Massive activation of coagulation and fibrinolysis

                                                      Does not allow for compensatory efforts

                                                      Rapid depletion of coagulation factors inhibitors and platelets

                                                      Thrombosis multiple organ failures

                                                      Bleeding complications and shock

                                                      Physiopathology of DIC ndash Overt DIC Findings

                                                      Thrombin generation

                                                      Thrombosis

                                                      Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                                                      Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                                                      Plasmin generationHemorrhage

                                                      bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                                                      bull Tachycardia hypotension edema

                                                      Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                      Pathogenesis Pathways in DIC

                                                      Cytokines

                                                      TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                                                      fibrin inadequateformation fibrin removal

                                                      Fibrin deposition

                                                      Inflammation

                                                      Coagulation

                                                      Stago Celebrates Lab Week 2017

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                                                      HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

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                                                      BREAK

                                                      Diagnostic and Management Approach for DIC

                                                      Diagnosis of DIC

                                                      Clinical diagnosis is obvious in cases of overt DIC

                                                      Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                                      Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                                      Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                                      Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                                      Important to recognize simultaneous formation of thrombin and plasmin

                                                      Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                      Lab Diagnosis of DIC ndash Screening Tests

                                                      Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                      Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                                      fibrinogen level) repeat testing assesses progression

                                                      Screening tests not clinically specific or sensitive for DIC

                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                      Laboratory Changes in Overt DIC

                                                      DIC Diagnostic Practices Over Time

                                                      Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                      British Journal of Haematology Overt DIC Score

                                                      Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                      ISTH Step by Step DIC Algorithm

                                                      Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                      US Based Validation of ISTH DIC Score

                                                      When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                      Differential Diagnosis in DIC

                                                      aHUS atypical hemolytic uremic syndrome

                                                      HUS hemolytic uremic syndrome

                                                      HIT heparin-induced thrombocytopenia

                                                      ITP immune thrombocytopenic purpura

                                                      TTP thrombotic thrombocytopenic purpura

                                                      DIC and MAHA

                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                      lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                      When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                      DIC Management Goals

                                                      Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                      Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                      DIC Management and Treatment

                                                      Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                      Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                      requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                      Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                      DIC Management Strategies

                                                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                      Anticoagulant Factor Concentrate Treatment

                                                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                      Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                      Anticoagulant Factor Concentrate Treatment Trials

                                                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                      Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                      Markers of Thrombin amp Plasmin Generation in DIC

                                                      D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                      Cut-off value

                                                      Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                      degradation products Sensitive assay typically with cutoff adapted for DIC

                                                      D-dimer FDPs and DIC

                                                      D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                      Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                      Follow Up of DIC State of Disease

                                                      Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                      Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                      FMD-Dimer in DIC Major Differences

                                                      onset of thrombosis

                                                      days

                                                      Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                      FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                      D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                      of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                      0

                                                      20

                                                      40

                                                      60

                                                      80

                                                      100

                                                      94 85 90N = 62

                                                      Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                      Positivity of Test Results ISTH Score and Disease State

                                                      Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                      Red bar positive for 2 points of DIC score

                                                      Pink bar positive for 1-2 points of DIC score

                                                      HT hematopoietic tumor

                                                      IF infection

                                                      SC solid cancer

                                                      Markers in Patients with or without DIC

                                                      Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                      HT hematopoietic tumorIF infectionSC solid cancer

                                                      Comparing an Automated FM vs Manual FSP Test

                                                      Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                      Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                      Automated (Mitsubishi) vs Automated (Stago)

                                                      In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                      Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                      In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                      In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                      In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                      Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                      No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                      Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                      Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                      Non Overt DIC Overt DIC

                                                      AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                      Trends in Markers of DIC for Different Patients

                                                      Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                      Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                      Trends in Markers of DIC for Different Patients

                                                      Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                      FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                      28 day outcome survival

                                                      28 day outcome death

                                                      Determination of Cutoffs of FM and D-dimer in DIC

                                                      Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                      Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                      Determination of Cutoffs of FM and D-dimer in DIC

                                                      Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                      Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                      DIC Case Studies

                                                      Case Study 1 - Presentation

                                                      18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                      Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                      WBC count 77 KμL 423 ndash 907 x KμL

                                                      RBC count 17 MμL 137 ndash 175 x MμL

                                                      Hemoglobin 67 gdL 137 ndash 175 gdL

                                                      Hematocrit 195 401 ndash 510

                                                      MCV 95 fL 790 ndash 922 fL

                                                      MPV 12 fL 94 ndash 124 fL

                                                      Platelet count 9 KμL 161 ndash 347 KμL

                                                      Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                      Lymphocytes monocytes eosinophils basophils all below normal range

                                                      PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                      APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                      Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                      D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                      Case Study 1 ndash Microscopy

                                                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                      Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                      Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                      DIC due to TF release by APL blasts

                                                      Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                      Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                      20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                      Case Study 2 ndash Presentation

                                                      TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                      PT 30 sec 113 ndash 146 sec

                                                      APTT 75 sec 25 ndash 34 sec

                                                      D-dimer 078 microgml FEU lt050 microgml FEU

                                                      Fibrinogen 92 mgdl 150-400 mgdl

                                                      pH 728 738 to 742

                                                      PaO2 570 mmHg 80-100 mmHg

                                                      WBC 33 times 103mm3 40-11 times 103mm3

                                                      ALT 111 IUL 0ndash34 IUL

                                                      AST 61 IUL 0ndash34 IUL

                                                      BUN 303 mgdL 08-13 mgdL

                                                      Case Study 2 ndash Lab Results

                                                      Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                      Case Study 2 ndash Diagnosis

                                                      60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                      Case Study 3 ndash Presentation

                                                      TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                      PT 228 sec 113 ndash 146 sec

                                                      APTT 45 sec 25 ndash 34 sec

                                                      D-dimer 080 microgml FEU lt050 microgmL FEU

                                                      Fibrinogen 82 mgdL 150-400 mgdL

                                                      FV Normal 70-120

                                                      FVII Normal 55-170

                                                      FVIII Normal 60-150

                                                      Protein C Normal 70-130

                                                      Hb 134 gdL 14-16 gdL

                                                      WBC 81 times 103mm3 40-11 times 103mm3

                                                      ALT 32 IUL 0ndash34 IUL

                                                      AST 28 IUL 0ndash34 IUL

                                                      BUN 09 mgdL 08-13 mgdL

                                                      Case Study 3 ndash Lab Results

                                                      Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                      Case Study 3 ndash Diagnosis and Therapy

                                                      Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                      Case Study 4 ndash Presentation

                                                      TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                      PT 28 sec 113 ndash 146 sec

                                                      APTT 71 sec 25 ndash 34 sec

                                                      D-dimer 31 microgmL FEU lt050 microgml FEU

                                                      Fibrinogen 92 mgdL 150-400 mgdl

                                                      FV Normal 70-120

                                                      FVII Normal 55-170

                                                      FVIII Normal 60-150

                                                      Protein C Normal 70-130

                                                      Hb 158 gdL 14-16 gdL

                                                      WBC 71 times 103mm3 40-11 times 103mm3

                                                      ALT 60 IUL 0ndash34 IUL

                                                      AST 47 IUL 0ndash34 IUL

                                                      BUN 38 mgdL 08-13 mgdL

                                                      Case Study 4 ndash Lab Results

                                                      Lyme disease with DICProvide antibiotics with supportive measures

                                                      Case Study 4 ndash Diagnosis

                                                      55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                      Case Study 5 ndash Presentation

                                                      Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                      Case Study 5 ndash Lab Results and Time Course

                                                      Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                      TEST RESULT REFERENCE RANGE

                                                      Platelet count 33 x 109L 150-450 x 109L

                                                      PT 215 sec 103 ndash 128 sec

                                                      APTT 44 sec 26 ndash 36 sec

                                                      D-dimer 20 microgmL FEU lt025 microgml FEU

                                                      Fibrinogen 34 mgdL 200-375 mgdl

                                                      FII FV FVIII Low Not reported (NR)

                                                      FVII FIX FX vWF Normal NR

                                                      Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                      DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                      dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                      (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                      (D) Illustration demonstrating repair

                                                      Case Study 5 ndash Diagnosis and Treatment

                                                      Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                      29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                      Case Study 6 ndash Presentation

                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                      Case Study 6 ndash Lab Results

                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                      TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                      PT 63 sec gt control 113 ndash 146 sec

                                                      INR 658 1 ndash 125

                                                      APTT 80 sec gt control 25 ndash 34 sec

                                                      D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                      Urine exam Proteinuria and hematuria 150-400 mgdl

                                                      Albumin 28 gdL NR

                                                      Hb 58 gdL NR

                                                      LDH 1196 UL NR

                                                      SGPT 144 IU NR

                                                      SGOT 88 IU NR

                                                      Bilirubin 32 mgdL NR

                                                      DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                      day postop

                                                      Case Study 6 ndash Diagnosis and Treatment

                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                      HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                      Case Study 6 ndash Discussion

                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                      44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                      Case Study 7 ndash Presentation

                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                      On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                      Case Study 7 ndash Presentation

                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                      Case Study 7 ndash Lab Results vs Time

                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                      Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                      Case Study 7 ndash Diagnosis and Treatment

                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                      On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                      Case Study 7 ndash Diagnosis and Treatment

                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                      DIC Take Home Messages

                                                      Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                      Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                      DIC

                                                      Thank you Questions

                                                      • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                      • Learning Objectives
                                                      • Slide Number 3
                                                      • Slide Number 4
                                                      • Slide Number 5
                                                      • Slide Number 6
                                                      • Slide Number 7
                                                      • Slide Number 8
                                                      • Wound Sealing
                                                      • The Three Steps of Hemostasis
                                                      • Vessel Wall
                                                      • Slide Number 12
                                                      • Slide Number 13
                                                      • Platelet Structure UnactivatedActivated
                                                      • Primary Hemostasis
                                                      • Primary Hemostasis Assays
                                                      • Slide Number 17
                                                      • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                      • Slide Number 19
                                                      • Coagulation factors
                                                      • Coagulation Assay Mechanisms
                                                      • Slide Number 22
                                                      • Fibrin Formation
                                                      • Slide Number 24
                                                      • Fibrinolysis Overview
                                                      • Fibrinolysis Overview
                                                      • Slide Number 27
                                                      • Fibrinolysis Releases D-dimers
                                                      • Basic Pathophysiology of DIC
                                                      • Disseminated Intravascular Coagulation (DIC)
                                                      • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                      • Clinical Conditions Associated With DIC
                                                      • Frequency of DIC in Selected Disease States
                                                      • Underlying Diseases in DIC Patients
                                                      • Slide Number 36
                                                      • Slide Number 37
                                                      • Slide Number 38
                                                      • Slide Number 39
                                                      • Pathophysiology of DIC
                                                      • Pathogenesis of DIC in Sepsis
                                                      • Host Response in Severe Sepsis
                                                      • Organ Failure in Severe Sepsis
                                                      • Mechanism of DIC in Organ Failure
                                                      • Interaction of Inflammation and Coagulation in Sepsis
                                                      • Slide Number 47
                                                      • Diverse and Opposing Effects of Thrombin
                                                      • Coagulation and Fibrinolysis in DIC
                                                      • Mechanism of DIC
                                                      • Pathophysiology of DIC
                                                      • Pathophysiology of DIC - Mechanism
                                                      • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                      • Sub-Acute and Non-Overt DIC Clinical Findings
                                                      • Pathophysiology of Overt DIC
                                                      • Physiopathology of DIC ndash Overt DIC Findings
                                                      • Slide Number 57
                                                      • Slide Number 58
                                                      • Slide Number 59
                                                      • Slide Number 60
                                                      • Slide Number 61
                                                      • BREAK
                                                      • Diagnostic and Management Approach for DIC
                                                      • Diagnosis of DIC
                                                      • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                      • Lab Diagnosis of DIC ndash Screening Tests
                                                      • Slide Number 67
                                                      • Slide Number 68
                                                      • British Journal of Haematology Overt DIC Score
                                                      • Slide Number 70
                                                      • Slide Number 71
                                                      • Slide Number 72
                                                      • Slide Number 73
                                                      • DIC Management Goals
                                                      • DIC Management and Treatment
                                                      • DIC Management Strategies
                                                      • Anticoagulant Factor Concentrate Treatment
                                                      • Anticoagulant Factor Concentrate Treatment Trials
                                                      • Markers of Thrombin amp Plasmin Generation in DIC
                                                      • D-dimer FDPs and DIC
                                                      • D-Dimer and FDPs in DIC
                                                      • Follow Up of DIC State of Disease
                                                      • FMD-Dimer in DIC Major Differences
                                                      • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                      • Slide Number 85
                                                      • Slide Number 86
                                                      • Comparing an Automated FM vs Manual FSP Test
                                                      • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                      • Slide Number 94
                                                      • Slide Number 95
                                                      • Slide Number 96
                                                      • Slide Number 97
                                                      • Slide Number 98
                                                      • Slide Number 99
                                                      • DIC Case Studies
                                                      • Case Study 1 - Presentation
                                                      • Case Study 1 ndash Lab Results
                                                      • Case Study 1 ndash Microscopy
                                                      • Case Study 1 ndash Diagnosis and Therapy
                                                      • Slide Number 105
                                                      • Slide Number 106
                                                      • Slide Number 107
                                                      • Slide Number 108
                                                      • Slide Number 109
                                                      • Slide Number 110
                                                      • Slide Number 111
                                                      • Slide Number 112
                                                      • Slide Number 113
                                                      • Slide Number 114
                                                      • Slide Number 115
                                                      • Slide Number 116
                                                      • Slide Number 117
                                                      • Slide Number 118
                                                      • Slide Number 119
                                                      • Slide Number 120
                                                      • Slide Number 121
                                                      • Slide Number 122
                                                      • Slide Number 123
                                                      • Slide Number 124
                                                      • Slide Number 125
                                                      • DIC Take Home Messages
                                                      • Slide Number 127
                                                      • Slide Number 128

                                                        Fibrinolysis Releases D-dimers

                                                        D-dimer presence fibrin has been formed and digested in patients body

                                                        Normal D-dimer level no thrombosis occurred in the patient

                                                        Basic Pathophysiology of DIC

                                                        Disseminated Intravascular Coagulation (DIC)

                                                        Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management

                                                        Clinical Manifestations of DICOrgan Ischemic Hemorrhagic

                                                        Skin Pupura Fulminans Petechiae

                                                        Gangrene Echymoses

                                                        Acral cyanosis Oozing

                                                        CNS Deliriumcoma Intracranial

                                                        Infarcts Bleeding

                                                        Renal OliguriaAzotemia Hematuria

                                                        Cortical Necrosis

                                                        Cardiovascular Myocardial dysfunction

                                                        Pulmonary DyspneaHypoxia Hemorrhagic lung

                                                        Infarct

                                                        Gastrointestinal Ulcers infarcts Massive hemorrhage

                                                        Endocrine Adrenal infarcts

                                                        Purpura Fulminans with DIC Due to Meningococcal Sepsis

                                                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                        Clinical Conditions Associated With DIC

                                                        Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                        Frequency of DIC in Selected Disease States

                                                        Disease Frequency

                                                        Gram-negative sepsis 30-50

                                                        Severe trauma and systemic inflammation 50-70

                                                        Metastasized tumors 15

                                                        Abruptio placentaamniotic fluid embolism 50

                                                        Severe preeclampsia 7

                                                        Giant hemangioma 25

                                                        Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                                        Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017

                                                        Underlying Diseases in DIC Patients

                                                        In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively

                                                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                        Epidemiology of DIC

                                                        Impact of DIC Status on Mortality - 1

                                                        Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8

                                                        Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC

                                                        Impact of DIC Status on Mortality - 2

                                                        Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                                        Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients

                                                        Impact of Age on Mortality in DIC Patients

                                                        Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                                        Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)

                                                        Pathophysiology of DIC

                                                        Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                        Pathogenesis of DIC in Sepsis

                                                        Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15

                                                        Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC

                                                        Host Response in Severe Sepsis

                                                        Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral

                                                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                        Organ Failure in Severe Sepsis

                                                        Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure

                                                        Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51

                                                        Mechanism of DIC in Organ Failure

                                                        Underlying condition(sepsis trauma)

                                                        Cytokines

                                                        TF-mediatedactivation of coagulation

                                                        Depression of inhibitory systems

                                                        Reducesfibrinolysis

                                                        Fibrin deposition

                                                        Organ failure

                                                        Inadequate fibrin removal

                                                        Fibrinformation

                                                        Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )

                                                        Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705

                                                        Interaction of Inflammation and Coagulation in Sepsis

                                                        Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines

                                                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                        Mechanism of Multiple Organ Failure in DIC

                                                        Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

                                                        Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

                                                        lipopolysaccharides

                                                        cytokines

                                                        coagulation activation

                                                        mononuclear cell

                                                        tissue factor

                                                        Diverse and Opposing Effects of Thrombin

                                                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                        Coagulation and Fibrinolysis in DIC

                                                        Soluble fibrin Polymer

                                                        XIIIa

                                                        D-Dimer

                                                        E

                                                        Fibrin clot

                                                        Fibrin Degradation Products

                                                        Fibrinogen Thrombin

                                                        Fibrinogen Degradation

                                                        Products

                                                        D E

                                                        Plasmin

                                                        DFM + fibrinopeptides

                                                        Soluble FM ComplexesPre-throm

                                                        boticPost-throm

                                                        botic

                                                        Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

                                                        Mechanism of DIC

                                                        THROMBOSIS

                                                        Fibrin

                                                        Blood activationEndothelial lysisTF expression

                                                        BLEEDING

                                                        FDPs

                                                        D-Dimer

                                                        Plasmin

                                                        Pathophysiology of DIC

                                                        1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

                                                        thromboplastin influx of activated cells (monocytes macrophages)

                                                        Results in an intravascular deposition of fibrin

                                                        Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

                                                        Second step Consumption and depletion of coagulation factors inhibitors (Protein C

                                                        Protein S AT) and platelets Local fibrinolytic response

                                                        bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

                                                        FDP and D-Dimer

                                                        Bleeding

                                                        Pathophysiology of DIC - Mechanism

                                                        Systemic activation of coagulation

                                                        Intravasculardepositionof fibrin

                                                        Thrombosis of small and midsize vessels

                                                        and organ failure

                                                        Depletion of platelets and

                                                        coagulation factors

                                                        Bleeding

                                                        Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                                        Pathophysiology of DIC ndash 2 Types of Clinical pictures

                                                        Chronic = non - overt DICMay be unrecognized clinically

                                                        Acute = overt DIClife threatening bleedingor multiple organ failure

                                                        Sub-Acute and Non-Overt DIC Clinical Findings

                                                        Compensated non-overt DIC Steady low level or intermittent activation

                                                        bull Compensated by increased production of coagulation components and platelets

                                                        Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                                                        Risk of decompensation leading to overt DIC

                                                        Pathophysiology of Overt DIC

                                                        Massive activation of coagulation and fibrinolysis

                                                        Does not allow for compensatory efforts

                                                        Rapid depletion of coagulation factors inhibitors and platelets

                                                        Thrombosis multiple organ failures

                                                        Bleeding complications and shock

                                                        Physiopathology of DIC ndash Overt DIC Findings

                                                        Thrombin generation

                                                        Thrombosis

                                                        Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                                                        Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                                                        Plasmin generationHemorrhage

                                                        bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                                                        bull Tachycardia hypotension edema

                                                        Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                        Pathogenesis Pathways in DIC

                                                        Cytokines

                                                        TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                                                        fibrin inadequateformation fibrin removal

                                                        Fibrin deposition

                                                        Inflammation

                                                        Coagulation

                                                        Stago Celebrates Lab Week 2017

                                                        NA

                                                        Stago 247 Educational Webinar Sites

                                                        wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                                                        wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                                                        Stago Educational Apps

                                                        HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                                                        iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                                                        BREAK

                                                        Diagnostic and Management Approach for DIC

                                                        Diagnosis of DIC

                                                        Clinical diagnosis is obvious in cases of overt DIC

                                                        Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                                        Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                                        Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                                        Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                                        Important to recognize simultaneous formation of thrombin and plasmin

                                                        Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                        Lab Diagnosis of DIC ndash Screening Tests

                                                        Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                        Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                                        fibrinogen level) repeat testing assesses progression

                                                        Screening tests not clinically specific or sensitive for DIC

                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                        Laboratory Changes in Overt DIC

                                                        DIC Diagnostic Practices Over Time

                                                        Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                        British Journal of Haematology Overt DIC Score

                                                        Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                        ISTH Step by Step DIC Algorithm

                                                        Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                        US Based Validation of ISTH DIC Score

                                                        When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                        Differential Diagnosis in DIC

                                                        aHUS atypical hemolytic uremic syndrome

                                                        HUS hemolytic uremic syndrome

                                                        HIT heparin-induced thrombocytopenia

                                                        ITP immune thrombocytopenic purpura

                                                        TTP thrombotic thrombocytopenic purpura

                                                        DIC and MAHA

                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                        lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                        When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                        DIC Management Goals

                                                        Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                        Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                        DIC Management and Treatment

                                                        Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                        Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                        requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                        Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                        DIC Management Strategies

                                                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                        Anticoagulant Factor Concentrate Treatment

                                                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                        Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                        Anticoagulant Factor Concentrate Treatment Trials

                                                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                        Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                        Markers of Thrombin amp Plasmin Generation in DIC

                                                        D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                        Cut-off value

                                                        Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                        degradation products Sensitive assay typically with cutoff adapted for DIC

                                                        D-dimer FDPs and DIC

                                                        D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                        Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                        Follow Up of DIC State of Disease

                                                        Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                        Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                        FMD-Dimer in DIC Major Differences

                                                        onset of thrombosis

                                                        days

                                                        Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                        FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                        D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                        of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                        0

                                                        20

                                                        40

                                                        60

                                                        80

                                                        100

                                                        94 85 90N = 62

                                                        Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                        Positivity of Test Results ISTH Score and Disease State

                                                        Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                        Red bar positive for 2 points of DIC score

                                                        Pink bar positive for 1-2 points of DIC score

                                                        HT hematopoietic tumor

                                                        IF infection

                                                        SC solid cancer

                                                        Markers in Patients with or without DIC

                                                        Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                        HT hematopoietic tumorIF infectionSC solid cancer

                                                        Comparing an Automated FM vs Manual FSP Test

                                                        Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                        Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                        Automated (Mitsubishi) vs Automated (Stago)

                                                        In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                        Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                        In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                        In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                        In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                        Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                        No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                        Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                        Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                        Non Overt DIC Overt DIC

                                                        AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                        Trends in Markers of DIC for Different Patients

                                                        Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                        Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                        Trends in Markers of DIC for Different Patients

                                                        Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                        FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                        28 day outcome survival

                                                        28 day outcome death

                                                        Determination of Cutoffs of FM and D-dimer in DIC

                                                        Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                        Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                        Determination of Cutoffs of FM and D-dimer in DIC

                                                        Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                        Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                        DIC Case Studies

                                                        Case Study 1 - Presentation

                                                        18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                        Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                        WBC count 77 KμL 423 ndash 907 x KμL

                                                        RBC count 17 MμL 137 ndash 175 x MμL

                                                        Hemoglobin 67 gdL 137 ndash 175 gdL

                                                        Hematocrit 195 401 ndash 510

                                                        MCV 95 fL 790 ndash 922 fL

                                                        MPV 12 fL 94 ndash 124 fL

                                                        Platelet count 9 KμL 161 ndash 347 KμL

                                                        Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                        Lymphocytes monocytes eosinophils basophils all below normal range

                                                        PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                        APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                        Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                        D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                        Case Study 1 ndash Microscopy

                                                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                        Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                        Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                        DIC due to TF release by APL blasts

                                                        Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                        Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                        20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                        Case Study 2 ndash Presentation

                                                        TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                        PT 30 sec 113 ndash 146 sec

                                                        APTT 75 sec 25 ndash 34 sec

                                                        D-dimer 078 microgml FEU lt050 microgml FEU

                                                        Fibrinogen 92 mgdl 150-400 mgdl

                                                        pH 728 738 to 742

                                                        PaO2 570 mmHg 80-100 mmHg

                                                        WBC 33 times 103mm3 40-11 times 103mm3

                                                        ALT 111 IUL 0ndash34 IUL

                                                        AST 61 IUL 0ndash34 IUL

                                                        BUN 303 mgdL 08-13 mgdL

                                                        Case Study 2 ndash Lab Results

                                                        Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                        Case Study 2 ndash Diagnosis

                                                        60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                        Case Study 3 ndash Presentation

                                                        TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                        PT 228 sec 113 ndash 146 sec

                                                        APTT 45 sec 25 ndash 34 sec

                                                        D-dimer 080 microgml FEU lt050 microgmL FEU

                                                        Fibrinogen 82 mgdL 150-400 mgdL

                                                        FV Normal 70-120

                                                        FVII Normal 55-170

                                                        FVIII Normal 60-150

                                                        Protein C Normal 70-130

                                                        Hb 134 gdL 14-16 gdL

                                                        WBC 81 times 103mm3 40-11 times 103mm3

                                                        ALT 32 IUL 0ndash34 IUL

                                                        AST 28 IUL 0ndash34 IUL

                                                        BUN 09 mgdL 08-13 mgdL

                                                        Case Study 3 ndash Lab Results

                                                        Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                        Case Study 3 ndash Diagnosis and Therapy

                                                        Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                        Case Study 4 ndash Presentation

                                                        TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                        PT 28 sec 113 ndash 146 sec

                                                        APTT 71 sec 25 ndash 34 sec

                                                        D-dimer 31 microgmL FEU lt050 microgml FEU

                                                        Fibrinogen 92 mgdL 150-400 mgdl

                                                        FV Normal 70-120

                                                        FVII Normal 55-170

                                                        FVIII Normal 60-150

                                                        Protein C Normal 70-130

                                                        Hb 158 gdL 14-16 gdL

                                                        WBC 71 times 103mm3 40-11 times 103mm3

                                                        ALT 60 IUL 0ndash34 IUL

                                                        AST 47 IUL 0ndash34 IUL

                                                        BUN 38 mgdL 08-13 mgdL

                                                        Case Study 4 ndash Lab Results

                                                        Lyme disease with DICProvide antibiotics with supportive measures

                                                        Case Study 4 ndash Diagnosis

                                                        55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                        Case Study 5 ndash Presentation

                                                        Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                        Case Study 5 ndash Lab Results and Time Course

                                                        Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                        TEST RESULT REFERENCE RANGE

                                                        Platelet count 33 x 109L 150-450 x 109L

                                                        PT 215 sec 103 ndash 128 sec

                                                        APTT 44 sec 26 ndash 36 sec

                                                        D-dimer 20 microgmL FEU lt025 microgml FEU

                                                        Fibrinogen 34 mgdL 200-375 mgdl

                                                        FII FV FVIII Low Not reported (NR)

                                                        FVII FIX FX vWF Normal NR

                                                        Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                        DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                        dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                        (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                        (D) Illustration demonstrating repair

                                                        Case Study 5 ndash Diagnosis and Treatment

                                                        Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                        29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                        Case Study 6 ndash Presentation

                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                        Case Study 6 ndash Lab Results

                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                        TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                        PT 63 sec gt control 113 ndash 146 sec

                                                        INR 658 1 ndash 125

                                                        APTT 80 sec gt control 25 ndash 34 sec

                                                        D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                        Urine exam Proteinuria and hematuria 150-400 mgdl

                                                        Albumin 28 gdL NR

                                                        Hb 58 gdL NR

                                                        LDH 1196 UL NR

                                                        SGPT 144 IU NR

                                                        SGOT 88 IU NR

                                                        Bilirubin 32 mgdL NR

                                                        DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                        day postop

                                                        Case Study 6 ndash Diagnosis and Treatment

                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                        HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                        Case Study 6 ndash Discussion

                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                        44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                        Case Study 7 ndash Presentation

                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                        On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                        Case Study 7 ndash Presentation

                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                        Case Study 7 ndash Lab Results vs Time

                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                        Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                        Case Study 7 ndash Diagnosis and Treatment

                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                        On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                        Case Study 7 ndash Diagnosis and Treatment

                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                        DIC Take Home Messages

                                                        Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                        Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                        DIC

                                                        Thank you Questions

                                                        • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                        • Learning Objectives
                                                        • Slide Number 3
                                                        • Slide Number 4
                                                        • Slide Number 5
                                                        • Slide Number 6
                                                        • Slide Number 7
                                                        • Slide Number 8
                                                        • Wound Sealing
                                                        • The Three Steps of Hemostasis
                                                        • Vessel Wall
                                                        • Slide Number 12
                                                        • Slide Number 13
                                                        • Platelet Structure UnactivatedActivated
                                                        • Primary Hemostasis
                                                        • Primary Hemostasis Assays
                                                        • Slide Number 17
                                                        • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                        • Slide Number 19
                                                        • Coagulation factors
                                                        • Coagulation Assay Mechanisms
                                                        • Slide Number 22
                                                        • Fibrin Formation
                                                        • Slide Number 24
                                                        • Fibrinolysis Overview
                                                        • Fibrinolysis Overview
                                                        • Slide Number 27
                                                        • Fibrinolysis Releases D-dimers
                                                        • Basic Pathophysiology of DIC
                                                        • Disseminated Intravascular Coagulation (DIC)
                                                        • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                        • Clinical Conditions Associated With DIC
                                                        • Frequency of DIC in Selected Disease States
                                                        • Underlying Diseases in DIC Patients
                                                        • Slide Number 36
                                                        • Slide Number 37
                                                        • Slide Number 38
                                                        • Slide Number 39
                                                        • Pathophysiology of DIC
                                                        • Pathogenesis of DIC in Sepsis
                                                        • Host Response in Severe Sepsis
                                                        • Organ Failure in Severe Sepsis
                                                        • Mechanism of DIC in Organ Failure
                                                        • Interaction of Inflammation and Coagulation in Sepsis
                                                        • Slide Number 47
                                                        • Diverse and Opposing Effects of Thrombin
                                                        • Coagulation and Fibrinolysis in DIC
                                                        • Mechanism of DIC
                                                        • Pathophysiology of DIC
                                                        • Pathophysiology of DIC - Mechanism
                                                        • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                        • Sub-Acute and Non-Overt DIC Clinical Findings
                                                        • Pathophysiology of Overt DIC
                                                        • Physiopathology of DIC ndash Overt DIC Findings
                                                        • Slide Number 57
                                                        • Slide Number 58
                                                        • Slide Number 59
                                                        • Slide Number 60
                                                        • Slide Number 61
                                                        • BREAK
                                                        • Diagnostic and Management Approach for DIC
                                                        • Diagnosis of DIC
                                                        • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                        • Lab Diagnosis of DIC ndash Screening Tests
                                                        • Slide Number 67
                                                        • Slide Number 68
                                                        • British Journal of Haematology Overt DIC Score
                                                        • Slide Number 70
                                                        • Slide Number 71
                                                        • Slide Number 72
                                                        • Slide Number 73
                                                        • DIC Management Goals
                                                        • DIC Management and Treatment
                                                        • DIC Management Strategies
                                                        • Anticoagulant Factor Concentrate Treatment
                                                        • Anticoagulant Factor Concentrate Treatment Trials
                                                        • Markers of Thrombin amp Plasmin Generation in DIC
                                                        • D-dimer FDPs and DIC
                                                        • D-Dimer and FDPs in DIC
                                                        • Follow Up of DIC State of Disease
                                                        • FMD-Dimer in DIC Major Differences
                                                        • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                        • Slide Number 85
                                                        • Slide Number 86
                                                        • Comparing an Automated FM vs Manual FSP Test
                                                        • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                        • Slide Number 94
                                                        • Slide Number 95
                                                        • Slide Number 96
                                                        • Slide Number 97
                                                        • Slide Number 98
                                                        • Slide Number 99
                                                        • DIC Case Studies
                                                        • Case Study 1 - Presentation
                                                        • Case Study 1 ndash Lab Results
                                                        • Case Study 1 ndash Microscopy
                                                        • Case Study 1 ndash Diagnosis and Therapy
                                                        • Slide Number 105
                                                        • Slide Number 106
                                                        • Slide Number 107
                                                        • Slide Number 108
                                                        • Slide Number 109
                                                        • Slide Number 110
                                                        • Slide Number 111
                                                        • Slide Number 112
                                                        • Slide Number 113
                                                        • Slide Number 114
                                                        • Slide Number 115
                                                        • Slide Number 116
                                                        • Slide Number 117
                                                        • Slide Number 118
                                                        • Slide Number 119
                                                        • Slide Number 120
                                                        • Slide Number 121
                                                        • Slide Number 122
                                                        • Slide Number 123
                                                        • Slide Number 124
                                                        • Slide Number 125
                                                        • DIC Take Home Messages
                                                        • Slide Number 127
                                                        • Slide Number 128

                                                          Basic Pathophysiology of DIC

                                                          Disseminated Intravascular Coagulation (DIC)

                                                          Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management

                                                          Clinical Manifestations of DICOrgan Ischemic Hemorrhagic

                                                          Skin Pupura Fulminans Petechiae

                                                          Gangrene Echymoses

                                                          Acral cyanosis Oozing

                                                          CNS Deliriumcoma Intracranial

                                                          Infarcts Bleeding

                                                          Renal OliguriaAzotemia Hematuria

                                                          Cortical Necrosis

                                                          Cardiovascular Myocardial dysfunction

                                                          Pulmonary DyspneaHypoxia Hemorrhagic lung

                                                          Infarct

                                                          Gastrointestinal Ulcers infarcts Massive hemorrhage

                                                          Endocrine Adrenal infarcts

                                                          Purpura Fulminans with DIC Due to Meningococcal Sepsis

                                                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                          Clinical Conditions Associated With DIC

                                                          Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                          Frequency of DIC in Selected Disease States

                                                          Disease Frequency

                                                          Gram-negative sepsis 30-50

                                                          Severe trauma and systemic inflammation 50-70

                                                          Metastasized tumors 15

                                                          Abruptio placentaamniotic fluid embolism 50

                                                          Severe preeclampsia 7

                                                          Giant hemangioma 25

                                                          Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                                          Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017

                                                          Underlying Diseases in DIC Patients

                                                          In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively

                                                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                          Epidemiology of DIC

                                                          Impact of DIC Status on Mortality - 1

                                                          Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8

                                                          Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC

                                                          Impact of DIC Status on Mortality - 2

                                                          Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                                          Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients

                                                          Impact of Age on Mortality in DIC Patients

                                                          Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                                          Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)

                                                          Pathophysiology of DIC

                                                          Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                          Pathogenesis of DIC in Sepsis

                                                          Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15

                                                          Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC

                                                          Host Response in Severe Sepsis

                                                          Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral

                                                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                          Organ Failure in Severe Sepsis

                                                          Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure

                                                          Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51

                                                          Mechanism of DIC in Organ Failure

                                                          Underlying condition(sepsis trauma)

                                                          Cytokines

                                                          TF-mediatedactivation of coagulation

                                                          Depression of inhibitory systems

                                                          Reducesfibrinolysis

                                                          Fibrin deposition

                                                          Organ failure

                                                          Inadequate fibrin removal

                                                          Fibrinformation

                                                          Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )

                                                          Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705

                                                          Interaction of Inflammation and Coagulation in Sepsis

                                                          Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines

                                                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                          Mechanism of Multiple Organ Failure in DIC

                                                          Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

                                                          Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

                                                          lipopolysaccharides

                                                          cytokines

                                                          coagulation activation

                                                          mononuclear cell

                                                          tissue factor

                                                          Diverse and Opposing Effects of Thrombin

                                                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                          Coagulation and Fibrinolysis in DIC

                                                          Soluble fibrin Polymer

                                                          XIIIa

                                                          D-Dimer

                                                          E

                                                          Fibrin clot

                                                          Fibrin Degradation Products

                                                          Fibrinogen Thrombin

                                                          Fibrinogen Degradation

                                                          Products

                                                          D E

                                                          Plasmin

                                                          DFM + fibrinopeptides

                                                          Soluble FM ComplexesPre-throm

                                                          boticPost-throm

                                                          botic

                                                          Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

                                                          Mechanism of DIC

                                                          THROMBOSIS

                                                          Fibrin

                                                          Blood activationEndothelial lysisTF expression

                                                          BLEEDING

                                                          FDPs

                                                          D-Dimer

                                                          Plasmin

                                                          Pathophysiology of DIC

                                                          1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

                                                          thromboplastin influx of activated cells (monocytes macrophages)

                                                          Results in an intravascular deposition of fibrin

                                                          Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

                                                          Second step Consumption and depletion of coagulation factors inhibitors (Protein C

                                                          Protein S AT) and platelets Local fibrinolytic response

                                                          bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

                                                          FDP and D-Dimer

                                                          Bleeding

                                                          Pathophysiology of DIC - Mechanism

                                                          Systemic activation of coagulation

                                                          Intravasculardepositionof fibrin

                                                          Thrombosis of small and midsize vessels

                                                          and organ failure

                                                          Depletion of platelets and

                                                          coagulation factors

                                                          Bleeding

                                                          Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                                          Pathophysiology of DIC ndash 2 Types of Clinical pictures

                                                          Chronic = non - overt DICMay be unrecognized clinically

                                                          Acute = overt DIClife threatening bleedingor multiple organ failure

                                                          Sub-Acute and Non-Overt DIC Clinical Findings

                                                          Compensated non-overt DIC Steady low level or intermittent activation

                                                          bull Compensated by increased production of coagulation components and platelets

                                                          Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                                                          Risk of decompensation leading to overt DIC

                                                          Pathophysiology of Overt DIC

                                                          Massive activation of coagulation and fibrinolysis

                                                          Does not allow for compensatory efforts

                                                          Rapid depletion of coagulation factors inhibitors and platelets

                                                          Thrombosis multiple organ failures

                                                          Bleeding complications and shock

                                                          Physiopathology of DIC ndash Overt DIC Findings

                                                          Thrombin generation

                                                          Thrombosis

                                                          Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                                                          Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                                                          Plasmin generationHemorrhage

                                                          bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                                                          bull Tachycardia hypotension edema

                                                          Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                          Pathogenesis Pathways in DIC

                                                          Cytokines

                                                          TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                                                          fibrin inadequateformation fibrin removal

                                                          Fibrin deposition

                                                          Inflammation

                                                          Coagulation

                                                          Stago Celebrates Lab Week 2017

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                                                          wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                                                          wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

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                                                          HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                                                          iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                                                          BREAK

                                                          Diagnostic and Management Approach for DIC

                                                          Diagnosis of DIC

                                                          Clinical diagnosis is obvious in cases of overt DIC

                                                          Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                                          Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                                          Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                                          Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                                          Important to recognize simultaneous formation of thrombin and plasmin

                                                          Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                          Lab Diagnosis of DIC ndash Screening Tests

                                                          Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                          Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                                          fibrinogen level) repeat testing assesses progression

                                                          Screening tests not clinically specific or sensitive for DIC

                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                          Laboratory Changes in Overt DIC

                                                          DIC Diagnostic Practices Over Time

                                                          Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                          British Journal of Haematology Overt DIC Score

                                                          Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                          ISTH Step by Step DIC Algorithm

                                                          Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                          US Based Validation of ISTH DIC Score

                                                          When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                          Differential Diagnosis in DIC

                                                          aHUS atypical hemolytic uremic syndrome

                                                          HUS hemolytic uremic syndrome

                                                          HIT heparin-induced thrombocytopenia

                                                          ITP immune thrombocytopenic purpura

                                                          TTP thrombotic thrombocytopenic purpura

                                                          DIC and MAHA

                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                          lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                          When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                          DIC Management Goals

                                                          Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                          Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                          DIC Management and Treatment

                                                          Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                          Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                          requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                          Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                          DIC Management Strategies

                                                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                          Anticoagulant Factor Concentrate Treatment

                                                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                          Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                          Anticoagulant Factor Concentrate Treatment Trials

                                                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                          Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                          Markers of Thrombin amp Plasmin Generation in DIC

                                                          D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                          Cut-off value

                                                          Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                          degradation products Sensitive assay typically with cutoff adapted for DIC

                                                          D-dimer FDPs and DIC

                                                          D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                          Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                          Follow Up of DIC State of Disease

                                                          Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                          Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                          FMD-Dimer in DIC Major Differences

                                                          onset of thrombosis

                                                          days

                                                          Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                          FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                          D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                          of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                          0

                                                          20

                                                          40

                                                          60

                                                          80

                                                          100

                                                          94 85 90N = 62

                                                          Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                          Positivity of Test Results ISTH Score and Disease State

                                                          Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                          Red bar positive for 2 points of DIC score

                                                          Pink bar positive for 1-2 points of DIC score

                                                          HT hematopoietic tumor

                                                          IF infection

                                                          SC solid cancer

                                                          Markers in Patients with or without DIC

                                                          Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                          HT hematopoietic tumorIF infectionSC solid cancer

                                                          Comparing an Automated FM vs Manual FSP Test

                                                          Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                          Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                          Automated (Mitsubishi) vs Automated (Stago)

                                                          In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                          Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                          In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                          In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                          In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                          Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                          No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                          Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                          Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                          Non Overt DIC Overt DIC

                                                          AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                          Trends in Markers of DIC for Different Patients

                                                          Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                          Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                          Trends in Markers of DIC for Different Patients

                                                          Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                          FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                          28 day outcome survival

                                                          28 day outcome death

                                                          Determination of Cutoffs of FM and D-dimer in DIC

                                                          Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                          Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                          Determination of Cutoffs of FM and D-dimer in DIC

                                                          Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                          Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                          DIC Case Studies

                                                          Case Study 1 - Presentation

                                                          18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                          Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                          WBC count 77 KμL 423 ndash 907 x KμL

                                                          RBC count 17 MμL 137 ndash 175 x MμL

                                                          Hemoglobin 67 gdL 137 ndash 175 gdL

                                                          Hematocrit 195 401 ndash 510

                                                          MCV 95 fL 790 ndash 922 fL

                                                          MPV 12 fL 94 ndash 124 fL

                                                          Platelet count 9 KμL 161 ndash 347 KμL

                                                          Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                          Lymphocytes monocytes eosinophils basophils all below normal range

                                                          PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                          APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                          Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                          D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                          Case Study 1 ndash Microscopy

                                                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                          Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                          Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                          DIC due to TF release by APL blasts

                                                          Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                          Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                          20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                          Case Study 2 ndash Presentation

                                                          TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                          PT 30 sec 113 ndash 146 sec

                                                          APTT 75 sec 25 ndash 34 sec

                                                          D-dimer 078 microgml FEU lt050 microgml FEU

                                                          Fibrinogen 92 mgdl 150-400 mgdl

                                                          pH 728 738 to 742

                                                          PaO2 570 mmHg 80-100 mmHg

                                                          WBC 33 times 103mm3 40-11 times 103mm3

                                                          ALT 111 IUL 0ndash34 IUL

                                                          AST 61 IUL 0ndash34 IUL

                                                          BUN 303 mgdL 08-13 mgdL

                                                          Case Study 2 ndash Lab Results

                                                          Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                          Case Study 2 ndash Diagnosis

                                                          60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                          Case Study 3 ndash Presentation

                                                          TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                          PT 228 sec 113 ndash 146 sec

                                                          APTT 45 sec 25 ndash 34 sec

                                                          D-dimer 080 microgml FEU lt050 microgmL FEU

                                                          Fibrinogen 82 mgdL 150-400 mgdL

                                                          FV Normal 70-120

                                                          FVII Normal 55-170

                                                          FVIII Normal 60-150

                                                          Protein C Normal 70-130

                                                          Hb 134 gdL 14-16 gdL

                                                          WBC 81 times 103mm3 40-11 times 103mm3

                                                          ALT 32 IUL 0ndash34 IUL

                                                          AST 28 IUL 0ndash34 IUL

                                                          BUN 09 mgdL 08-13 mgdL

                                                          Case Study 3 ndash Lab Results

                                                          Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                          Case Study 3 ndash Diagnosis and Therapy

                                                          Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                          Case Study 4 ndash Presentation

                                                          TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                          PT 28 sec 113 ndash 146 sec

                                                          APTT 71 sec 25 ndash 34 sec

                                                          D-dimer 31 microgmL FEU lt050 microgml FEU

                                                          Fibrinogen 92 mgdL 150-400 mgdl

                                                          FV Normal 70-120

                                                          FVII Normal 55-170

                                                          FVIII Normal 60-150

                                                          Protein C Normal 70-130

                                                          Hb 158 gdL 14-16 gdL

                                                          WBC 71 times 103mm3 40-11 times 103mm3

                                                          ALT 60 IUL 0ndash34 IUL

                                                          AST 47 IUL 0ndash34 IUL

                                                          BUN 38 mgdL 08-13 mgdL

                                                          Case Study 4 ndash Lab Results

                                                          Lyme disease with DICProvide antibiotics with supportive measures

                                                          Case Study 4 ndash Diagnosis

                                                          55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                          Case Study 5 ndash Presentation

                                                          Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                          Case Study 5 ndash Lab Results and Time Course

                                                          Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                          TEST RESULT REFERENCE RANGE

                                                          Platelet count 33 x 109L 150-450 x 109L

                                                          PT 215 sec 103 ndash 128 sec

                                                          APTT 44 sec 26 ndash 36 sec

                                                          D-dimer 20 microgmL FEU lt025 microgml FEU

                                                          Fibrinogen 34 mgdL 200-375 mgdl

                                                          FII FV FVIII Low Not reported (NR)

                                                          FVII FIX FX vWF Normal NR

                                                          Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                          DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                          dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                          (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                          (D) Illustration demonstrating repair

                                                          Case Study 5 ndash Diagnosis and Treatment

                                                          Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                          29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                          Case Study 6 ndash Presentation

                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                          Case Study 6 ndash Lab Results

                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                          TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                          PT 63 sec gt control 113 ndash 146 sec

                                                          INR 658 1 ndash 125

                                                          APTT 80 sec gt control 25 ndash 34 sec

                                                          D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                          Urine exam Proteinuria and hematuria 150-400 mgdl

                                                          Albumin 28 gdL NR

                                                          Hb 58 gdL NR

                                                          LDH 1196 UL NR

                                                          SGPT 144 IU NR

                                                          SGOT 88 IU NR

                                                          Bilirubin 32 mgdL NR

                                                          DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                          day postop

                                                          Case Study 6 ndash Diagnosis and Treatment

                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                          HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                          Case Study 6 ndash Discussion

                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                          44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                          Case Study 7 ndash Presentation

                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                          On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                          Case Study 7 ndash Presentation

                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                          Case Study 7 ndash Lab Results vs Time

                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                          Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                          Case Study 7 ndash Diagnosis and Treatment

                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                          On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                          Case Study 7 ndash Diagnosis and Treatment

                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                          DIC Take Home Messages

                                                          Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                          Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                          DIC

                                                          Thank you Questions

                                                          • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                          • Learning Objectives
                                                          • Slide Number 3
                                                          • Slide Number 4
                                                          • Slide Number 5
                                                          • Slide Number 6
                                                          • Slide Number 7
                                                          • Slide Number 8
                                                          • Wound Sealing
                                                          • The Three Steps of Hemostasis
                                                          • Vessel Wall
                                                          • Slide Number 12
                                                          • Slide Number 13
                                                          • Platelet Structure UnactivatedActivated
                                                          • Primary Hemostasis
                                                          • Primary Hemostasis Assays
                                                          • Slide Number 17
                                                          • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                          • Slide Number 19
                                                          • Coagulation factors
                                                          • Coagulation Assay Mechanisms
                                                          • Slide Number 22
                                                          • Fibrin Formation
                                                          • Slide Number 24
                                                          • Fibrinolysis Overview
                                                          • Fibrinolysis Overview
                                                          • Slide Number 27
                                                          • Fibrinolysis Releases D-dimers
                                                          • Basic Pathophysiology of DIC
                                                          • Disseminated Intravascular Coagulation (DIC)
                                                          • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                          • Clinical Conditions Associated With DIC
                                                          • Frequency of DIC in Selected Disease States
                                                          • Underlying Diseases in DIC Patients
                                                          • Slide Number 36
                                                          • Slide Number 37
                                                          • Slide Number 38
                                                          • Slide Number 39
                                                          • Pathophysiology of DIC
                                                          • Pathogenesis of DIC in Sepsis
                                                          • Host Response in Severe Sepsis
                                                          • Organ Failure in Severe Sepsis
                                                          • Mechanism of DIC in Organ Failure
                                                          • Interaction of Inflammation and Coagulation in Sepsis
                                                          • Slide Number 47
                                                          • Diverse and Opposing Effects of Thrombin
                                                          • Coagulation and Fibrinolysis in DIC
                                                          • Mechanism of DIC
                                                          • Pathophysiology of DIC
                                                          • Pathophysiology of DIC - Mechanism
                                                          • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                          • Sub-Acute and Non-Overt DIC Clinical Findings
                                                          • Pathophysiology of Overt DIC
                                                          • Physiopathology of DIC ndash Overt DIC Findings
                                                          • Slide Number 57
                                                          • Slide Number 58
                                                          • Slide Number 59
                                                          • Slide Number 60
                                                          • Slide Number 61
                                                          • BREAK
                                                          • Diagnostic and Management Approach for DIC
                                                          • Diagnosis of DIC
                                                          • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                          • Lab Diagnosis of DIC ndash Screening Tests
                                                          • Slide Number 67
                                                          • Slide Number 68
                                                          • British Journal of Haematology Overt DIC Score
                                                          • Slide Number 70
                                                          • Slide Number 71
                                                          • Slide Number 72
                                                          • Slide Number 73
                                                          • DIC Management Goals
                                                          • DIC Management and Treatment
                                                          • DIC Management Strategies
                                                          • Anticoagulant Factor Concentrate Treatment
                                                          • Anticoagulant Factor Concentrate Treatment Trials
                                                          • Markers of Thrombin amp Plasmin Generation in DIC
                                                          • D-dimer FDPs and DIC
                                                          • D-Dimer and FDPs in DIC
                                                          • Follow Up of DIC State of Disease
                                                          • FMD-Dimer in DIC Major Differences
                                                          • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                          • Slide Number 85
                                                          • Slide Number 86
                                                          • Comparing an Automated FM vs Manual FSP Test
                                                          • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                          • Slide Number 94
                                                          • Slide Number 95
                                                          • Slide Number 96
                                                          • Slide Number 97
                                                          • Slide Number 98
                                                          • Slide Number 99
                                                          • DIC Case Studies
                                                          • Case Study 1 - Presentation
                                                          • Case Study 1 ndash Lab Results
                                                          • Case Study 1 ndash Microscopy
                                                          • Case Study 1 ndash Diagnosis and Therapy
                                                          • Slide Number 105
                                                          • Slide Number 106
                                                          • Slide Number 107
                                                          • Slide Number 108
                                                          • Slide Number 109
                                                          • Slide Number 110
                                                          • Slide Number 111
                                                          • Slide Number 112
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                                                          • Slide Number 114
                                                          • Slide Number 115
                                                          • Slide Number 116
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                                                          • Slide Number 118
                                                          • Slide Number 119
                                                          • Slide Number 120
                                                          • Slide Number 121
                                                          • Slide Number 122
                                                          • Slide Number 123
                                                          • Slide Number 124
                                                          • Slide Number 125
                                                          • DIC Take Home Messages
                                                          • Slide Number 127
                                                          • Slide Number 128

                                                            Disseminated Intravascular Coagulation (DIC)

                                                            Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management

                                                            Clinical Manifestations of DICOrgan Ischemic Hemorrhagic

                                                            Skin Pupura Fulminans Petechiae

                                                            Gangrene Echymoses

                                                            Acral cyanosis Oozing

                                                            CNS Deliriumcoma Intracranial

                                                            Infarcts Bleeding

                                                            Renal OliguriaAzotemia Hematuria

                                                            Cortical Necrosis

                                                            Cardiovascular Myocardial dysfunction

                                                            Pulmonary DyspneaHypoxia Hemorrhagic lung

                                                            Infarct

                                                            Gastrointestinal Ulcers infarcts Massive hemorrhage

                                                            Endocrine Adrenal infarcts

                                                            Purpura Fulminans with DIC Due to Meningococcal Sepsis

                                                            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                            Clinical Conditions Associated With DIC

                                                            Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                            Frequency of DIC in Selected Disease States

                                                            Disease Frequency

                                                            Gram-negative sepsis 30-50

                                                            Severe trauma and systemic inflammation 50-70

                                                            Metastasized tumors 15

                                                            Abruptio placentaamniotic fluid embolism 50

                                                            Severe preeclampsia 7

                                                            Giant hemangioma 25

                                                            Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                                            Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017

                                                            Underlying Diseases in DIC Patients

                                                            In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively

                                                            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                            Epidemiology of DIC

                                                            Impact of DIC Status on Mortality - 1

                                                            Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8

                                                            Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC

                                                            Impact of DIC Status on Mortality - 2

                                                            Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                                            Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients

                                                            Impact of Age on Mortality in DIC Patients

                                                            Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                                            Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)

                                                            Pathophysiology of DIC

                                                            Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                            Pathogenesis of DIC in Sepsis

                                                            Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15

                                                            Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC

                                                            Host Response in Severe Sepsis

                                                            Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral

                                                            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                            Organ Failure in Severe Sepsis

                                                            Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure

                                                            Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51

                                                            Mechanism of DIC in Organ Failure

                                                            Underlying condition(sepsis trauma)

                                                            Cytokines

                                                            TF-mediatedactivation of coagulation

                                                            Depression of inhibitory systems

                                                            Reducesfibrinolysis

                                                            Fibrin deposition

                                                            Organ failure

                                                            Inadequate fibrin removal

                                                            Fibrinformation

                                                            Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )

                                                            Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705

                                                            Interaction of Inflammation and Coagulation in Sepsis

                                                            Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines

                                                            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                            Mechanism of Multiple Organ Failure in DIC

                                                            Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

                                                            Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

                                                            lipopolysaccharides

                                                            cytokines

                                                            coagulation activation

                                                            mononuclear cell

                                                            tissue factor

                                                            Diverse and Opposing Effects of Thrombin

                                                            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                            Coagulation and Fibrinolysis in DIC

                                                            Soluble fibrin Polymer

                                                            XIIIa

                                                            D-Dimer

                                                            E

                                                            Fibrin clot

                                                            Fibrin Degradation Products

                                                            Fibrinogen Thrombin

                                                            Fibrinogen Degradation

                                                            Products

                                                            D E

                                                            Plasmin

                                                            DFM + fibrinopeptides

                                                            Soluble FM ComplexesPre-throm

                                                            boticPost-throm

                                                            botic

                                                            Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

                                                            Mechanism of DIC

                                                            THROMBOSIS

                                                            Fibrin

                                                            Blood activationEndothelial lysisTF expression

                                                            BLEEDING

                                                            FDPs

                                                            D-Dimer

                                                            Plasmin

                                                            Pathophysiology of DIC

                                                            1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

                                                            thromboplastin influx of activated cells (monocytes macrophages)

                                                            Results in an intravascular deposition of fibrin

                                                            Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

                                                            Second step Consumption and depletion of coagulation factors inhibitors (Protein C

                                                            Protein S AT) and platelets Local fibrinolytic response

                                                            bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

                                                            FDP and D-Dimer

                                                            Bleeding

                                                            Pathophysiology of DIC - Mechanism

                                                            Systemic activation of coagulation

                                                            Intravasculardepositionof fibrin

                                                            Thrombosis of small and midsize vessels

                                                            and organ failure

                                                            Depletion of platelets and

                                                            coagulation factors

                                                            Bleeding

                                                            Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                                            Pathophysiology of DIC ndash 2 Types of Clinical pictures

                                                            Chronic = non - overt DICMay be unrecognized clinically

                                                            Acute = overt DIClife threatening bleedingor multiple organ failure

                                                            Sub-Acute and Non-Overt DIC Clinical Findings

                                                            Compensated non-overt DIC Steady low level or intermittent activation

                                                            bull Compensated by increased production of coagulation components and platelets

                                                            Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                                                            Risk of decompensation leading to overt DIC

                                                            Pathophysiology of Overt DIC

                                                            Massive activation of coagulation and fibrinolysis

                                                            Does not allow for compensatory efforts

                                                            Rapid depletion of coagulation factors inhibitors and platelets

                                                            Thrombosis multiple organ failures

                                                            Bleeding complications and shock

                                                            Physiopathology of DIC ndash Overt DIC Findings

                                                            Thrombin generation

                                                            Thrombosis

                                                            Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                                                            Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                                                            Plasmin generationHemorrhage

                                                            bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                                                            bull Tachycardia hypotension edema

                                                            Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                            Pathogenesis Pathways in DIC

                                                            Cytokines

                                                            TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                                                            fibrin inadequateformation fibrin removal

                                                            Fibrin deposition

                                                            Inflammation

                                                            Coagulation

                                                            Stago Celebrates Lab Week 2017

                                                            NA

                                                            Stago 247 Educational Webinar Sites

                                                            wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                                                            wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                                                            Stago Educational Apps

                                                            HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                                                            iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                                                            BREAK

                                                            Diagnostic and Management Approach for DIC

                                                            Diagnosis of DIC

                                                            Clinical diagnosis is obvious in cases of overt DIC

                                                            Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                                            Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                                            Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                                            Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                                            Important to recognize simultaneous formation of thrombin and plasmin

                                                            Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                            Lab Diagnosis of DIC ndash Screening Tests

                                                            Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                            Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                                            fibrinogen level) repeat testing assesses progression

                                                            Screening tests not clinically specific or sensitive for DIC

                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                            Laboratory Changes in Overt DIC

                                                            DIC Diagnostic Practices Over Time

                                                            Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                            British Journal of Haematology Overt DIC Score

                                                            Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                            ISTH Step by Step DIC Algorithm

                                                            Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                            US Based Validation of ISTH DIC Score

                                                            When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                            Differential Diagnosis in DIC

                                                            aHUS atypical hemolytic uremic syndrome

                                                            HUS hemolytic uremic syndrome

                                                            HIT heparin-induced thrombocytopenia

                                                            ITP immune thrombocytopenic purpura

                                                            TTP thrombotic thrombocytopenic purpura

                                                            DIC and MAHA

                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                            lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                            When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                            DIC Management Goals

                                                            Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                            Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                            DIC Management and Treatment

                                                            Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                            Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                            requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                            Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                            DIC Management Strategies

                                                            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                            Anticoagulant Factor Concentrate Treatment

                                                            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                            Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                            Anticoagulant Factor Concentrate Treatment Trials

                                                            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                            Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                            Markers of Thrombin amp Plasmin Generation in DIC

                                                            D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                            Cut-off value

                                                            Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                            degradation products Sensitive assay typically with cutoff adapted for DIC

                                                            D-dimer FDPs and DIC

                                                            D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                            Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                            Follow Up of DIC State of Disease

                                                            Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                            Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                            FMD-Dimer in DIC Major Differences

                                                            onset of thrombosis

                                                            days

                                                            Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                            FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                            D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                            of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                            0

                                                            20

                                                            40

                                                            60

                                                            80

                                                            100

                                                            94 85 90N = 62

                                                            Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                            Positivity of Test Results ISTH Score and Disease State

                                                            Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                            Red bar positive for 2 points of DIC score

                                                            Pink bar positive for 1-2 points of DIC score

                                                            HT hematopoietic tumor

                                                            IF infection

                                                            SC solid cancer

                                                            Markers in Patients with or without DIC

                                                            Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                            HT hematopoietic tumorIF infectionSC solid cancer

                                                            Comparing an Automated FM vs Manual FSP Test

                                                            Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                            Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                            Automated (Mitsubishi) vs Automated (Stago)

                                                            In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                            Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                            In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                            In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                            In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                            Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                            No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                            Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                            Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                            Non Overt DIC Overt DIC

                                                            AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                            Trends in Markers of DIC for Different Patients

                                                            Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                            Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                            Trends in Markers of DIC for Different Patients

                                                            Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                            FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                            28 day outcome survival

                                                            28 day outcome death

                                                            Determination of Cutoffs of FM and D-dimer in DIC

                                                            Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                            Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                            Determination of Cutoffs of FM and D-dimer in DIC

                                                            Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                            Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                            DIC Case Studies

                                                            Case Study 1 - Presentation

                                                            18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                            Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                            WBC count 77 KμL 423 ndash 907 x KμL

                                                            RBC count 17 MμL 137 ndash 175 x MμL

                                                            Hemoglobin 67 gdL 137 ndash 175 gdL

                                                            Hematocrit 195 401 ndash 510

                                                            MCV 95 fL 790 ndash 922 fL

                                                            MPV 12 fL 94 ndash 124 fL

                                                            Platelet count 9 KμL 161 ndash 347 KμL

                                                            Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                            Lymphocytes monocytes eosinophils basophils all below normal range

                                                            PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                            APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                            Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                            D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                            Case Study 1 ndash Microscopy

                                                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                            Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                            Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                            DIC due to TF release by APL blasts

                                                            Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                            Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                            20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                            Case Study 2 ndash Presentation

                                                            TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                            PT 30 sec 113 ndash 146 sec

                                                            APTT 75 sec 25 ndash 34 sec

                                                            D-dimer 078 microgml FEU lt050 microgml FEU

                                                            Fibrinogen 92 mgdl 150-400 mgdl

                                                            pH 728 738 to 742

                                                            PaO2 570 mmHg 80-100 mmHg

                                                            WBC 33 times 103mm3 40-11 times 103mm3

                                                            ALT 111 IUL 0ndash34 IUL

                                                            AST 61 IUL 0ndash34 IUL

                                                            BUN 303 mgdL 08-13 mgdL

                                                            Case Study 2 ndash Lab Results

                                                            Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                            Case Study 2 ndash Diagnosis

                                                            60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                            Case Study 3 ndash Presentation

                                                            TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                            PT 228 sec 113 ndash 146 sec

                                                            APTT 45 sec 25 ndash 34 sec

                                                            D-dimer 080 microgml FEU lt050 microgmL FEU

                                                            Fibrinogen 82 mgdL 150-400 mgdL

                                                            FV Normal 70-120

                                                            FVII Normal 55-170

                                                            FVIII Normal 60-150

                                                            Protein C Normal 70-130

                                                            Hb 134 gdL 14-16 gdL

                                                            WBC 81 times 103mm3 40-11 times 103mm3

                                                            ALT 32 IUL 0ndash34 IUL

                                                            AST 28 IUL 0ndash34 IUL

                                                            BUN 09 mgdL 08-13 mgdL

                                                            Case Study 3 ndash Lab Results

                                                            Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                            Case Study 3 ndash Diagnosis and Therapy

                                                            Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                            Case Study 4 ndash Presentation

                                                            TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                            PT 28 sec 113 ndash 146 sec

                                                            APTT 71 sec 25 ndash 34 sec

                                                            D-dimer 31 microgmL FEU lt050 microgml FEU

                                                            Fibrinogen 92 mgdL 150-400 mgdl

                                                            FV Normal 70-120

                                                            FVII Normal 55-170

                                                            FVIII Normal 60-150

                                                            Protein C Normal 70-130

                                                            Hb 158 gdL 14-16 gdL

                                                            WBC 71 times 103mm3 40-11 times 103mm3

                                                            ALT 60 IUL 0ndash34 IUL

                                                            AST 47 IUL 0ndash34 IUL

                                                            BUN 38 mgdL 08-13 mgdL

                                                            Case Study 4 ndash Lab Results

                                                            Lyme disease with DICProvide antibiotics with supportive measures

                                                            Case Study 4 ndash Diagnosis

                                                            55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                            Case Study 5 ndash Presentation

                                                            Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                            Case Study 5 ndash Lab Results and Time Course

                                                            Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                            TEST RESULT REFERENCE RANGE

                                                            Platelet count 33 x 109L 150-450 x 109L

                                                            PT 215 sec 103 ndash 128 sec

                                                            APTT 44 sec 26 ndash 36 sec

                                                            D-dimer 20 microgmL FEU lt025 microgml FEU

                                                            Fibrinogen 34 mgdL 200-375 mgdl

                                                            FII FV FVIII Low Not reported (NR)

                                                            FVII FIX FX vWF Normal NR

                                                            Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                            DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                            dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                            (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                            (D) Illustration demonstrating repair

                                                            Case Study 5 ndash Diagnosis and Treatment

                                                            Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                            29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                            Case Study 6 ndash Presentation

                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                            Case Study 6 ndash Lab Results

                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                            TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                            PT 63 sec gt control 113 ndash 146 sec

                                                            INR 658 1 ndash 125

                                                            APTT 80 sec gt control 25 ndash 34 sec

                                                            D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                            Urine exam Proteinuria and hematuria 150-400 mgdl

                                                            Albumin 28 gdL NR

                                                            Hb 58 gdL NR

                                                            LDH 1196 UL NR

                                                            SGPT 144 IU NR

                                                            SGOT 88 IU NR

                                                            Bilirubin 32 mgdL NR

                                                            DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                            day postop

                                                            Case Study 6 ndash Diagnosis and Treatment

                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                            HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                            Case Study 6 ndash Discussion

                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                            44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                            Case Study 7 ndash Presentation

                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                            On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                            Case Study 7 ndash Presentation

                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                            Case Study 7 ndash Lab Results vs Time

                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                            Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                            Case Study 7 ndash Diagnosis and Treatment

                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                            On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                            Case Study 7 ndash Diagnosis and Treatment

                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                            DIC Take Home Messages

                                                            Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                            Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                            DIC

                                                            Thank you Questions

                                                            • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                            • Learning Objectives
                                                            • Slide Number 3
                                                            • Slide Number 4
                                                            • Slide Number 5
                                                            • Slide Number 6
                                                            • Slide Number 7
                                                            • Slide Number 8
                                                            • Wound Sealing
                                                            • The Three Steps of Hemostasis
                                                            • Vessel Wall
                                                            • Slide Number 12
                                                            • Slide Number 13
                                                            • Platelet Structure UnactivatedActivated
                                                            • Primary Hemostasis
                                                            • Primary Hemostasis Assays
                                                            • Slide Number 17
                                                            • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                            • Slide Number 19
                                                            • Coagulation factors
                                                            • Coagulation Assay Mechanisms
                                                            • Slide Number 22
                                                            • Fibrin Formation
                                                            • Slide Number 24
                                                            • Fibrinolysis Overview
                                                            • Fibrinolysis Overview
                                                            • Slide Number 27
                                                            • Fibrinolysis Releases D-dimers
                                                            • Basic Pathophysiology of DIC
                                                            • Disseminated Intravascular Coagulation (DIC)
                                                            • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                            • Clinical Conditions Associated With DIC
                                                            • Frequency of DIC in Selected Disease States
                                                            • Underlying Diseases in DIC Patients
                                                            • Slide Number 36
                                                            • Slide Number 37
                                                            • Slide Number 38
                                                            • Slide Number 39
                                                            • Pathophysiology of DIC
                                                            • Pathogenesis of DIC in Sepsis
                                                            • Host Response in Severe Sepsis
                                                            • Organ Failure in Severe Sepsis
                                                            • Mechanism of DIC in Organ Failure
                                                            • Interaction of Inflammation and Coagulation in Sepsis
                                                            • Slide Number 47
                                                            • Diverse and Opposing Effects of Thrombin
                                                            • Coagulation and Fibrinolysis in DIC
                                                            • Mechanism of DIC
                                                            • Pathophysiology of DIC
                                                            • Pathophysiology of DIC - Mechanism
                                                            • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                            • Sub-Acute and Non-Overt DIC Clinical Findings
                                                            • Pathophysiology of Overt DIC
                                                            • Physiopathology of DIC ndash Overt DIC Findings
                                                            • Slide Number 57
                                                            • Slide Number 58
                                                            • Slide Number 59
                                                            • Slide Number 60
                                                            • Slide Number 61
                                                            • BREAK
                                                            • Diagnostic and Management Approach for DIC
                                                            • Diagnosis of DIC
                                                            • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                            • Lab Diagnosis of DIC ndash Screening Tests
                                                            • Slide Number 67
                                                            • Slide Number 68
                                                            • British Journal of Haematology Overt DIC Score
                                                            • Slide Number 70
                                                            • Slide Number 71
                                                            • Slide Number 72
                                                            • Slide Number 73
                                                            • DIC Management Goals
                                                            • DIC Management and Treatment
                                                            • DIC Management Strategies
                                                            • Anticoagulant Factor Concentrate Treatment
                                                            • Anticoagulant Factor Concentrate Treatment Trials
                                                            • Markers of Thrombin amp Plasmin Generation in DIC
                                                            • D-dimer FDPs and DIC
                                                            • D-Dimer and FDPs in DIC
                                                            • Follow Up of DIC State of Disease
                                                            • FMD-Dimer in DIC Major Differences
                                                            • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                            • Slide Number 85
                                                            • Slide Number 86
                                                            • Comparing an Automated FM vs Manual FSP Test
                                                            • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                            • Slide Number 94
                                                            • Slide Number 95
                                                            • Slide Number 96
                                                            • Slide Number 97
                                                            • Slide Number 98
                                                            • Slide Number 99
                                                            • DIC Case Studies
                                                            • Case Study 1 - Presentation
                                                            • Case Study 1 ndash Lab Results
                                                            • Case Study 1 ndash Microscopy
                                                            • Case Study 1 ndash Diagnosis and Therapy
                                                            • Slide Number 105
                                                            • Slide Number 106
                                                            • Slide Number 107
                                                            • Slide Number 108
                                                            • Slide Number 109
                                                            • Slide Number 110
                                                            • Slide Number 111
                                                            • Slide Number 112
                                                            • Slide Number 113
                                                            • Slide Number 114
                                                            • Slide Number 115
                                                            • Slide Number 116
                                                            • Slide Number 117
                                                            • Slide Number 118
                                                            • Slide Number 119
                                                            • Slide Number 120
                                                            • Slide Number 121
                                                            • Slide Number 122
                                                            • Slide Number 123
                                                            • Slide Number 124
                                                            • Slide Number 125
                                                            • DIC Take Home Messages
                                                            • Slide Number 127
                                                            • Slide Number 128

                                                              Clinical Manifestations of DICOrgan Ischemic Hemorrhagic

                                                              Skin Pupura Fulminans Petechiae

                                                              Gangrene Echymoses

                                                              Acral cyanosis Oozing

                                                              CNS Deliriumcoma Intracranial

                                                              Infarcts Bleeding

                                                              Renal OliguriaAzotemia Hematuria

                                                              Cortical Necrosis

                                                              Cardiovascular Myocardial dysfunction

                                                              Pulmonary DyspneaHypoxia Hemorrhagic lung

                                                              Infarct

                                                              Gastrointestinal Ulcers infarcts Massive hemorrhage

                                                              Endocrine Adrenal infarcts

                                                              Purpura Fulminans with DIC Due to Meningococcal Sepsis

                                                              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                              Clinical Conditions Associated With DIC

                                                              Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                              Frequency of DIC in Selected Disease States

                                                              Disease Frequency

                                                              Gram-negative sepsis 30-50

                                                              Severe trauma and systemic inflammation 50-70

                                                              Metastasized tumors 15

                                                              Abruptio placentaamniotic fluid embolism 50

                                                              Severe preeclampsia 7

                                                              Giant hemangioma 25

                                                              Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                                              Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017

                                                              Underlying Diseases in DIC Patients

                                                              In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively

                                                              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                              Epidemiology of DIC

                                                              Impact of DIC Status on Mortality - 1

                                                              Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8

                                                              Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC

                                                              Impact of DIC Status on Mortality - 2

                                                              Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                                              Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients

                                                              Impact of Age on Mortality in DIC Patients

                                                              Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                                              Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)

                                                              Pathophysiology of DIC

                                                              Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                              Pathogenesis of DIC in Sepsis

                                                              Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15

                                                              Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC

                                                              Host Response in Severe Sepsis

                                                              Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral

                                                              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                              Organ Failure in Severe Sepsis

                                                              Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure

                                                              Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51

                                                              Mechanism of DIC in Organ Failure

                                                              Underlying condition(sepsis trauma)

                                                              Cytokines

                                                              TF-mediatedactivation of coagulation

                                                              Depression of inhibitory systems

                                                              Reducesfibrinolysis

                                                              Fibrin deposition

                                                              Organ failure

                                                              Inadequate fibrin removal

                                                              Fibrinformation

                                                              Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )

                                                              Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705

                                                              Interaction of Inflammation and Coagulation in Sepsis

                                                              Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines

                                                              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                              Mechanism of Multiple Organ Failure in DIC

                                                              Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

                                                              Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

                                                              lipopolysaccharides

                                                              cytokines

                                                              coagulation activation

                                                              mononuclear cell

                                                              tissue factor

                                                              Diverse and Opposing Effects of Thrombin

                                                              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                              Coagulation and Fibrinolysis in DIC

                                                              Soluble fibrin Polymer

                                                              XIIIa

                                                              D-Dimer

                                                              E

                                                              Fibrin clot

                                                              Fibrin Degradation Products

                                                              Fibrinogen Thrombin

                                                              Fibrinogen Degradation

                                                              Products

                                                              D E

                                                              Plasmin

                                                              DFM + fibrinopeptides

                                                              Soluble FM ComplexesPre-throm

                                                              boticPost-throm

                                                              botic

                                                              Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

                                                              Mechanism of DIC

                                                              THROMBOSIS

                                                              Fibrin

                                                              Blood activationEndothelial lysisTF expression

                                                              BLEEDING

                                                              FDPs

                                                              D-Dimer

                                                              Plasmin

                                                              Pathophysiology of DIC

                                                              1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

                                                              thromboplastin influx of activated cells (monocytes macrophages)

                                                              Results in an intravascular deposition of fibrin

                                                              Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

                                                              Second step Consumption and depletion of coagulation factors inhibitors (Protein C

                                                              Protein S AT) and platelets Local fibrinolytic response

                                                              bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

                                                              FDP and D-Dimer

                                                              Bleeding

                                                              Pathophysiology of DIC - Mechanism

                                                              Systemic activation of coagulation

                                                              Intravasculardepositionof fibrin

                                                              Thrombosis of small and midsize vessels

                                                              and organ failure

                                                              Depletion of platelets and

                                                              coagulation factors

                                                              Bleeding

                                                              Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                                              Pathophysiology of DIC ndash 2 Types of Clinical pictures

                                                              Chronic = non - overt DICMay be unrecognized clinically

                                                              Acute = overt DIClife threatening bleedingor multiple organ failure

                                                              Sub-Acute and Non-Overt DIC Clinical Findings

                                                              Compensated non-overt DIC Steady low level or intermittent activation

                                                              bull Compensated by increased production of coagulation components and platelets

                                                              Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                                                              Risk of decompensation leading to overt DIC

                                                              Pathophysiology of Overt DIC

                                                              Massive activation of coagulation and fibrinolysis

                                                              Does not allow for compensatory efforts

                                                              Rapid depletion of coagulation factors inhibitors and platelets

                                                              Thrombosis multiple organ failures

                                                              Bleeding complications and shock

                                                              Physiopathology of DIC ndash Overt DIC Findings

                                                              Thrombin generation

                                                              Thrombosis

                                                              Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                                                              Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                                                              Plasmin generationHemorrhage

                                                              bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                                                              bull Tachycardia hypotension edema

                                                              Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                              Pathogenesis Pathways in DIC

                                                              Cytokines

                                                              TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                                                              fibrin inadequateformation fibrin removal

                                                              Fibrin deposition

                                                              Inflammation

                                                              Coagulation

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                                                              BREAK

                                                              Diagnostic and Management Approach for DIC

                                                              Diagnosis of DIC

                                                              Clinical diagnosis is obvious in cases of overt DIC

                                                              Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                                              Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                                              Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                                              Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                                              Important to recognize simultaneous formation of thrombin and plasmin

                                                              Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                              Lab Diagnosis of DIC ndash Screening Tests

                                                              Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                              Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                                              fibrinogen level) repeat testing assesses progression

                                                              Screening tests not clinically specific or sensitive for DIC

                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                              Laboratory Changes in Overt DIC

                                                              DIC Diagnostic Practices Over Time

                                                              Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                              British Journal of Haematology Overt DIC Score

                                                              Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                              ISTH Step by Step DIC Algorithm

                                                              Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                              US Based Validation of ISTH DIC Score

                                                              When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                              Differential Diagnosis in DIC

                                                              aHUS atypical hemolytic uremic syndrome

                                                              HUS hemolytic uremic syndrome

                                                              HIT heparin-induced thrombocytopenia

                                                              ITP immune thrombocytopenic purpura

                                                              TTP thrombotic thrombocytopenic purpura

                                                              DIC and MAHA

                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                              lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                              When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                              DIC Management Goals

                                                              Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                              Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                              DIC Management and Treatment

                                                              Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                              Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                              requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                              Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                              DIC Management Strategies

                                                              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                              Anticoagulant Factor Concentrate Treatment

                                                              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                              Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                              Anticoagulant Factor Concentrate Treatment Trials

                                                              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                              Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                              Markers of Thrombin amp Plasmin Generation in DIC

                                                              D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                              Cut-off value

                                                              Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                              degradation products Sensitive assay typically with cutoff adapted for DIC

                                                              D-dimer FDPs and DIC

                                                              D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                              Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                              Follow Up of DIC State of Disease

                                                              Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                              Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                              FMD-Dimer in DIC Major Differences

                                                              onset of thrombosis

                                                              days

                                                              Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                              FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                              D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                              of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                              0

                                                              20

                                                              40

                                                              60

                                                              80

                                                              100

                                                              94 85 90N = 62

                                                              Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                              Positivity of Test Results ISTH Score and Disease State

                                                              Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                              Red bar positive for 2 points of DIC score

                                                              Pink bar positive for 1-2 points of DIC score

                                                              HT hematopoietic tumor

                                                              IF infection

                                                              SC solid cancer

                                                              Markers in Patients with or without DIC

                                                              Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                              HT hematopoietic tumorIF infectionSC solid cancer

                                                              Comparing an Automated FM vs Manual FSP Test

                                                              Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                              Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                              Automated (Mitsubishi) vs Automated (Stago)

                                                              In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                              Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                              In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                              In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                              In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                              Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                              No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                              Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                              Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                              Non Overt DIC Overt DIC

                                                              AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                              Trends in Markers of DIC for Different Patients

                                                              Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                              Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                              Trends in Markers of DIC for Different Patients

                                                              Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                              FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                              28 day outcome survival

                                                              28 day outcome death

                                                              Determination of Cutoffs of FM and D-dimer in DIC

                                                              Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                              Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                              Determination of Cutoffs of FM and D-dimer in DIC

                                                              Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                              Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                              DIC Case Studies

                                                              Case Study 1 - Presentation

                                                              18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                              Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                              WBC count 77 KμL 423 ndash 907 x KμL

                                                              RBC count 17 MμL 137 ndash 175 x MμL

                                                              Hemoglobin 67 gdL 137 ndash 175 gdL

                                                              Hematocrit 195 401 ndash 510

                                                              MCV 95 fL 790 ndash 922 fL

                                                              MPV 12 fL 94 ndash 124 fL

                                                              Platelet count 9 KμL 161 ndash 347 KμL

                                                              Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                              Lymphocytes monocytes eosinophils basophils all below normal range

                                                              PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                              APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                              Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                              D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                              Case Study 1 ndash Microscopy

                                                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                              Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                              Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                              DIC due to TF release by APL blasts

                                                              Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                              Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                              20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                              Case Study 2 ndash Presentation

                                                              TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                              PT 30 sec 113 ndash 146 sec

                                                              APTT 75 sec 25 ndash 34 sec

                                                              D-dimer 078 microgml FEU lt050 microgml FEU

                                                              Fibrinogen 92 mgdl 150-400 mgdl

                                                              pH 728 738 to 742

                                                              PaO2 570 mmHg 80-100 mmHg

                                                              WBC 33 times 103mm3 40-11 times 103mm3

                                                              ALT 111 IUL 0ndash34 IUL

                                                              AST 61 IUL 0ndash34 IUL

                                                              BUN 303 mgdL 08-13 mgdL

                                                              Case Study 2 ndash Lab Results

                                                              Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                              Case Study 2 ndash Diagnosis

                                                              60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                              Case Study 3 ndash Presentation

                                                              TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                              PT 228 sec 113 ndash 146 sec

                                                              APTT 45 sec 25 ndash 34 sec

                                                              D-dimer 080 microgml FEU lt050 microgmL FEU

                                                              Fibrinogen 82 mgdL 150-400 mgdL

                                                              FV Normal 70-120

                                                              FVII Normal 55-170

                                                              FVIII Normal 60-150

                                                              Protein C Normal 70-130

                                                              Hb 134 gdL 14-16 gdL

                                                              WBC 81 times 103mm3 40-11 times 103mm3

                                                              ALT 32 IUL 0ndash34 IUL

                                                              AST 28 IUL 0ndash34 IUL

                                                              BUN 09 mgdL 08-13 mgdL

                                                              Case Study 3 ndash Lab Results

                                                              Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                              Case Study 3 ndash Diagnosis and Therapy

                                                              Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                              Case Study 4 ndash Presentation

                                                              TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                              PT 28 sec 113 ndash 146 sec

                                                              APTT 71 sec 25 ndash 34 sec

                                                              D-dimer 31 microgmL FEU lt050 microgml FEU

                                                              Fibrinogen 92 mgdL 150-400 mgdl

                                                              FV Normal 70-120

                                                              FVII Normal 55-170

                                                              FVIII Normal 60-150

                                                              Protein C Normal 70-130

                                                              Hb 158 gdL 14-16 gdL

                                                              WBC 71 times 103mm3 40-11 times 103mm3

                                                              ALT 60 IUL 0ndash34 IUL

                                                              AST 47 IUL 0ndash34 IUL

                                                              BUN 38 mgdL 08-13 mgdL

                                                              Case Study 4 ndash Lab Results

                                                              Lyme disease with DICProvide antibiotics with supportive measures

                                                              Case Study 4 ndash Diagnosis

                                                              55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                              Case Study 5 ndash Presentation

                                                              Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                              Case Study 5 ndash Lab Results and Time Course

                                                              Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                              TEST RESULT REFERENCE RANGE

                                                              Platelet count 33 x 109L 150-450 x 109L

                                                              PT 215 sec 103 ndash 128 sec

                                                              APTT 44 sec 26 ndash 36 sec

                                                              D-dimer 20 microgmL FEU lt025 microgml FEU

                                                              Fibrinogen 34 mgdL 200-375 mgdl

                                                              FII FV FVIII Low Not reported (NR)

                                                              FVII FIX FX vWF Normal NR

                                                              Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                              DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                              dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                              (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                              (D) Illustration demonstrating repair

                                                              Case Study 5 ndash Diagnosis and Treatment

                                                              Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                              29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                              Case Study 6 ndash Presentation

                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                              Case Study 6 ndash Lab Results

                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                              TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                              PT 63 sec gt control 113 ndash 146 sec

                                                              INR 658 1 ndash 125

                                                              APTT 80 sec gt control 25 ndash 34 sec

                                                              D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                              Urine exam Proteinuria and hematuria 150-400 mgdl

                                                              Albumin 28 gdL NR

                                                              Hb 58 gdL NR

                                                              LDH 1196 UL NR

                                                              SGPT 144 IU NR

                                                              SGOT 88 IU NR

                                                              Bilirubin 32 mgdL NR

                                                              DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                              day postop

                                                              Case Study 6 ndash Diagnosis and Treatment

                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                              HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                              Case Study 6 ndash Discussion

                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                              44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                              Case Study 7 ndash Presentation

                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                              On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                              Case Study 7 ndash Presentation

                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                              Case Study 7 ndash Lab Results vs Time

                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                              Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                              Case Study 7 ndash Diagnosis and Treatment

                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                              On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                              Case Study 7 ndash Diagnosis and Treatment

                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                              DIC Take Home Messages

                                                              Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                              Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                              DIC

                                                              Thank you Questions

                                                              • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                              • Learning Objectives
                                                              • Slide Number 3
                                                              • Slide Number 4
                                                              • Slide Number 5
                                                              • Slide Number 6
                                                              • Slide Number 7
                                                              • Slide Number 8
                                                              • Wound Sealing
                                                              • The Three Steps of Hemostasis
                                                              • Vessel Wall
                                                              • Slide Number 12
                                                              • Slide Number 13
                                                              • Platelet Structure UnactivatedActivated
                                                              • Primary Hemostasis
                                                              • Primary Hemostasis Assays
                                                              • Slide Number 17
                                                              • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                              • Slide Number 19
                                                              • Coagulation factors
                                                              • Coagulation Assay Mechanisms
                                                              • Slide Number 22
                                                              • Fibrin Formation
                                                              • Slide Number 24
                                                              • Fibrinolysis Overview
                                                              • Fibrinolysis Overview
                                                              • Slide Number 27
                                                              • Fibrinolysis Releases D-dimers
                                                              • Basic Pathophysiology of DIC
                                                              • Disseminated Intravascular Coagulation (DIC)
                                                              • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                              • Clinical Conditions Associated With DIC
                                                              • Frequency of DIC in Selected Disease States
                                                              • Underlying Diseases in DIC Patients
                                                              • Slide Number 36
                                                              • Slide Number 37
                                                              • Slide Number 38
                                                              • Slide Number 39
                                                              • Pathophysiology of DIC
                                                              • Pathogenesis of DIC in Sepsis
                                                              • Host Response in Severe Sepsis
                                                              • Organ Failure in Severe Sepsis
                                                              • Mechanism of DIC in Organ Failure
                                                              • Interaction of Inflammation and Coagulation in Sepsis
                                                              • Slide Number 47
                                                              • Diverse and Opposing Effects of Thrombin
                                                              • Coagulation and Fibrinolysis in DIC
                                                              • Mechanism of DIC
                                                              • Pathophysiology of DIC
                                                              • Pathophysiology of DIC - Mechanism
                                                              • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                              • Sub-Acute and Non-Overt DIC Clinical Findings
                                                              • Pathophysiology of Overt DIC
                                                              • Physiopathology of DIC ndash Overt DIC Findings
                                                              • Slide Number 57
                                                              • Slide Number 58
                                                              • Slide Number 59
                                                              • Slide Number 60
                                                              • Slide Number 61
                                                              • BREAK
                                                              • Diagnostic and Management Approach for DIC
                                                              • Diagnosis of DIC
                                                              • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                              • Lab Diagnosis of DIC ndash Screening Tests
                                                              • Slide Number 67
                                                              • Slide Number 68
                                                              • British Journal of Haematology Overt DIC Score
                                                              • Slide Number 70
                                                              • Slide Number 71
                                                              • Slide Number 72
                                                              • Slide Number 73
                                                              • DIC Management Goals
                                                              • DIC Management and Treatment
                                                              • DIC Management Strategies
                                                              • Anticoagulant Factor Concentrate Treatment
                                                              • Anticoagulant Factor Concentrate Treatment Trials
                                                              • Markers of Thrombin amp Plasmin Generation in DIC
                                                              • D-dimer FDPs and DIC
                                                              • D-Dimer and FDPs in DIC
                                                              • Follow Up of DIC State of Disease
                                                              • FMD-Dimer in DIC Major Differences
                                                              • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                              • Slide Number 85
                                                              • Slide Number 86
                                                              • Comparing an Automated FM vs Manual FSP Test
                                                              • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                              • Slide Number 94
                                                              • Slide Number 95
                                                              • Slide Number 96
                                                              • Slide Number 97
                                                              • Slide Number 98
                                                              • Slide Number 99
                                                              • DIC Case Studies
                                                              • Case Study 1 - Presentation
                                                              • Case Study 1 ndash Lab Results
                                                              • Case Study 1 ndash Microscopy
                                                              • Case Study 1 ndash Diagnosis and Therapy
                                                              • Slide Number 105
                                                              • Slide Number 106
                                                              • Slide Number 107
                                                              • Slide Number 108
                                                              • Slide Number 109
                                                              • Slide Number 110
                                                              • Slide Number 111
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                                                              • Slide Number 123
                                                              • Slide Number 124
                                                              • Slide Number 125
                                                              • DIC Take Home Messages
                                                              • Slide Number 127
                                                              • Slide Number 128

                                                                Purpura Fulminans with DIC Due to Meningococcal Sepsis

                                                                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                Clinical Conditions Associated With DIC

                                                                Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                Frequency of DIC in Selected Disease States

                                                                Disease Frequency

                                                                Gram-negative sepsis 30-50

                                                                Severe trauma and systemic inflammation 50-70

                                                                Metastasized tumors 15

                                                                Abruptio placentaamniotic fluid embolism 50

                                                                Severe preeclampsia 7

                                                                Giant hemangioma 25

                                                                Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                                                Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017

                                                                Underlying Diseases in DIC Patients

                                                                In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively

                                                                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                Epidemiology of DIC

                                                                Impact of DIC Status on Mortality - 1

                                                                Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8

                                                                Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC

                                                                Impact of DIC Status on Mortality - 2

                                                                Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                                                Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients

                                                                Impact of Age on Mortality in DIC Patients

                                                                Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                                                Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)

                                                                Pathophysiology of DIC

                                                                Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                Pathogenesis of DIC in Sepsis

                                                                Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15

                                                                Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC

                                                                Host Response in Severe Sepsis

                                                                Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral

                                                                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                Organ Failure in Severe Sepsis

                                                                Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure

                                                                Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51

                                                                Mechanism of DIC in Organ Failure

                                                                Underlying condition(sepsis trauma)

                                                                Cytokines

                                                                TF-mediatedactivation of coagulation

                                                                Depression of inhibitory systems

                                                                Reducesfibrinolysis

                                                                Fibrin deposition

                                                                Organ failure

                                                                Inadequate fibrin removal

                                                                Fibrinformation

                                                                Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )

                                                                Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705

                                                                Interaction of Inflammation and Coagulation in Sepsis

                                                                Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines

                                                                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                Mechanism of Multiple Organ Failure in DIC

                                                                Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

                                                                Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

                                                                lipopolysaccharides

                                                                cytokines

                                                                coagulation activation

                                                                mononuclear cell

                                                                tissue factor

                                                                Diverse and Opposing Effects of Thrombin

                                                                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                Coagulation and Fibrinolysis in DIC

                                                                Soluble fibrin Polymer

                                                                XIIIa

                                                                D-Dimer

                                                                E

                                                                Fibrin clot

                                                                Fibrin Degradation Products

                                                                Fibrinogen Thrombin

                                                                Fibrinogen Degradation

                                                                Products

                                                                D E

                                                                Plasmin

                                                                DFM + fibrinopeptides

                                                                Soluble FM ComplexesPre-throm

                                                                boticPost-throm

                                                                botic

                                                                Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

                                                                Mechanism of DIC

                                                                THROMBOSIS

                                                                Fibrin

                                                                Blood activationEndothelial lysisTF expression

                                                                BLEEDING

                                                                FDPs

                                                                D-Dimer

                                                                Plasmin

                                                                Pathophysiology of DIC

                                                                1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

                                                                thromboplastin influx of activated cells (monocytes macrophages)

                                                                Results in an intravascular deposition of fibrin

                                                                Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

                                                                Second step Consumption and depletion of coagulation factors inhibitors (Protein C

                                                                Protein S AT) and platelets Local fibrinolytic response

                                                                bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

                                                                FDP and D-Dimer

                                                                Bleeding

                                                                Pathophysiology of DIC - Mechanism

                                                                Systemic activation of coagulation

                                                                Intravasculardepositionof fibrin

                                                                Thrombosis of small and midsize vessels

                                                                and organ failure

                                                                Depletion of platelets and

                                                                coagulation factors

                                                                Bleeding

                                                                Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                                                Pathophysiology of DIC ndash 2 Types of Clinical pictures

                                                                Chronic = non - overt DICMay be unrecognized clinically

                                                                Acute = overt DIClife threatening bleedingor multiple organ failure

                                                                Sub-Acute and Non-Overt DIC Clinical Findings

                                                                Compensated non-overt DIC Steady low level or intermittent activation

                                                                bull Compensated by increased production of coagulation components and platelets

                                                                Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                                                                Risk of decompensation leading to overt DIC

                                                                Pathophysiology of Overt DIC

                                                                Massive activation of coagulation and fibrinolysis

                                                                Does not allow for compensatory efforts

                                                                Rapid depletion of coagulation factors inhibitors and platelets

                                                                Thrombosis multiple organ failures

                                                                Bleeding complications and shock

                                                                Physiopathology of DIC ndash Overt DIC Findings

                                                                Thrombin generation

                                                                Thrombosis

                                                                Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                                                                Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                                                                Plasmin generationHemorrhage

                                                                bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                                                                bull Tachycardia hypotension edema

                                                                Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                Pathogenesis Pathways in DIC

                                                                Cytokines

                                                                TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                                                                fibrin inadequateformation fibrin removal

                                                                Fibrin deposition

                                                                Inflammation

                                                                Coagulation

                                                                Stago Celebrates Lab Week 2017

                                                                NA

                                                                Stago 247 Educational Webinar Sites

                                                                wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                                                                wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                                                                Stago Educational Apps

                                                                HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                                                                iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                                                                BREAK

                                                                Diagnostic and Management Approach for DIC

                                                                Diagnosis of DIC

                                                                Clinical diagnosis is obvious in cases of overt DIC

                                                                Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                                                Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                                                Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                                                Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                                                Important to recognize simultaneous formation of thrombin and plasmin

                                                                Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                Lab Diagnosis of DIC ndash Screening Tests

                                                                Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                                                fibrinogen level) repeat testing assesses progression

                                                                Screening tests not clinically specific or sensitive for DIC

                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                Laboratory Changes in Overt DIC

                                                                DIC Diagnostic Practices Over Time

                                                                Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                British Journal of Haematology Overt DIC Score

                                                                Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                ISTH Step by Step DIC Algorithm

                                                                Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                                US Based Validation of ISTH DIC Score

                                                                When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                Differential Diagnosis in DIC

                                                                aHUS atypical hemolytic uremic syndrome

                                                                HUS hemolytic uremic syndrome

                                                                HIT heparin-induced thrombocytopenia

                                                                ITP immune thrombocytopenic purpura

                                                                TTP thrombotic thrombocytopenic purpura

                                                                DIC and MAHA

                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                                When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                                DIC Management Goals

                                                                Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                                DIC Management and Treatment

                                                                Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                                requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                                Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                                DIC Management Strategies

                                                                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                Anticoagulant Factor Concentrate Treatment

                                                                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                Anticoagulant Factor Concentrate Treatment Trials

                                                                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                Markers of Thrombin amp Plasmin Generation in DIC

                                                                D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                Cut-off value

                                                                Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                D-dimer FDPs and DIC

                                                                D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                Follow Up of DIC State of Disease

                                                                Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                FMD-Dimer in DIC Major Differences

                                                                onset of thrombosis

                                                                days

                                                                Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                0

                                                                20

                                                                40

                                                                60

                                                                80

                                                                100

                                                                94 85 90N = 62

                                                                Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                Positivity of Test Results ISTH Score and Disease State

                                                                Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                Red bar positive for 2 points of DIC score

                                                                Pink bar positive for 1-2 points of DIC score

                                                                HT hematopoietic tumor

                                                                IF infection

                                                                SC solid cancer

                                                                Markers in Patients with or without DIC

                                                                Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                HT hematopoietic tumorIF infectionSC solid cancer

                                                                Comparing an Automated FM vs Manual FSP Test

                                                                Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                Automated (Mitsubishi) vs Automated (Stago)

                                                                In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                Non Overt DIC Overt DIC

                                                                AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                Trends in Markers of DIC for Different Patients

                                                                Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                Trends in Markers of DIC for Different Patients

                                                                Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                28 day outcome survival

                                                                28 day outcome death

                                                                Determination of Cutoffs of FM and D-dimer in DIC

                                                                Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                Determination of Cutoffs of FM and D-dimer in DIC

                                                                Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                DIC Case Studies

                                                                Case Study 1 - Presentation

                                                                18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                WBC count 77 KμL 423 ndash 907 x KμL

                                                                RBC count 17 MμL 137 ndash 175 x MμL

                                                                Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                Hematocrit 195 401 ndash 510

                                                                MCV 95 fL 790 ndash 922 fL

                                                                MPV 12 fL 94 ndash 124 fL

                                                                Platelet count 9 KμL 161 ndash 347 KμL

                                                                Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                Lymphocytes monocytes eosinophils basophils all below normal range

                                                                PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                Case Study 1 ndash Microscopy

                                                                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                DIC due to TF release by APL blasts

                                                                Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                Case Study 2 ndash Presentation

                                                                TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                PT 30 sec 113 ndash 146 sec

                                                                APTT 75 sec 25 ndash 34 sec

                                                                D-dimer 078 microgml FEU lt050 microgml FEU

                                                                Fibrinogen 92 mgdl 150-400 mgdl

                                                                pH 728 738 to 742

                                                                PaO2 570 mmHg 80-100 mmHg

                                                                WBC 33 times 103mm3 40-11 times 103mm3

                                                                ALT 111 IUL 0ndash34 IUL

                                                                AST 61 IUL 0ndash34 IUL

                                                                BUN 303 mgdL 08-13 mgdL

                                                                Case Study 2 ndash Lab Results

                                                                Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                Case Study 2 ndash Diagnosis

                                                                60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                Case Study 3 ndash Presentation

                                                                TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                PT 228 sec 113 ndash 146 sec

                                                                APTT 45 sec 25 ndash 34 sec

                                                                D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                Fibrinogen 82 mgdL 150-400 mgdL

                                                                FV Normal 70-120

                                                                FVII Normal 55-170

                                                                FVIII Normal 60-150

                                                                Protein C Normal 70-130

                                                                Hb 134 gdL 14-16 gdL

                                                                WBC 81 times 103mm3 40-11 times 103mm3

                                                                ALT 32 IUL 0ndash34 IUL

                                                                AST 28 IUL 0ndash34 IUL

                                                                BUN 09 mgdL 08-13 mgdL

                                                                Case Study 3 ndash Lab Results

                                                                Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                Case Study 3 ndash Diagnosis and Therapy

                                                                Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                Case Study 4 ndash Presentation

                                                                TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                PT 28 sec 113 ndash 146 sec

                                                                APTT 71 sec 25 ndash 34 sec

                                                                D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                Fibrinogen 92 mgdL 150-400 mgdl

                                                                FV Normal 70-120

                                                                FVII Normal 55-170

                                                                FVIII Normal 60-150

                                                                Protein C Normal 70-130

                                                                Hb 158 gdL 14-16 gdL

                                                                WBC 71 times 103mm3 40-11 times 103mm3

                                                                ALT 60 IUL 0ndash34 IUL

                                                                AST 47 IUL 0ndash34 IUL

                                                                BUN 38 mgdL 08-13 mgdL

                                                                Case Study 4 ndash Lab Results

                                                                Lyme disease with DICProvide antibiotics with supportive measures

                                                                Case Study 4 ndash Diagnosis

                                                                55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                Case Study 5 ndash Presentation

                                                                Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                Case Study 5 ndash Lab Results and Time Course

                                                                Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                TEST RESULT REFERENCE RANGE

                                                                Platelet count 33 x 109L 150-450 x 109L

                                                                PT 215 sec 103 ndash 128 sec

                                                                APTT 44 sec 26 ndash 36 sec

                                                                D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                Fibrinogen 34 mgdL 200-375 mgdl

                                                                FII FV FVIII Low Not reported (NR)

                                                                FVII FIX FX vWF Normal NR

                                                                Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                (D) Illustration demonstrating repair

                                                                Case Study 5 ndash Diagnosis and Treatment

                                                                Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                Case Study 6 ndash Presentation

                                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                Case Study 6 ndash Lab Results

                                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                PT 63 sec gt control 113 ndash 146 sec

                                                                INR 658 1 ndash 125

                                                                APTT 80 sec gt control 25 ndash 34 sec

                                                                D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                Albumin 28 gdL NR

                                                                Hb 58 gdL NR

                                                                LDH 1196 UL NR

                                                                SGPT 144 IU NR

                                                                SGOT 88 IU NR

                                                                Bilirubin 32 mgdL NR

                                                                DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                day postop

                                                                Case Study 6 ndash Diagnosis and Treatment

                                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                Case Study 6 ndash Discussion

                                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                Case Study 7 ndash Presentation

                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                Case Study 7 ndash Presentation

                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                Case Study 7 ndash Lab Results vs Time

                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                Case Study 7 ndash Diagnosis and Treatment

                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                Case Study 7 ndash Diagnosis and Treatment

                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                DIC Take Home Messages

                                                                Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                DIC

                                                                Thank you Questions

                                                                • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                • Learning Objectives
                                                                • Slide Number 3
                                                                • Slide Number 4
                                                                • Slide Number 5
                                                                • Slide Number 6
                                                                • Slide Number 7
                                                                • Slide Number 8
                                                                • Wound Sealing
                                                                • The Three Steps of Hemostasis
                                                                • Vessel Wall
                                                                • Slide Number 12
                                                                • Slide Number 13
                                                                • Platelet Structure UnactivatedActivated
                                                                • Primary Hemostasis
                                                                • Primary Hemostasis Assays
                                                                • Slide Number 17
                                                                • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                • Slide Number 19
                                                                • Coagulation factors
                                                                • Coagulation Assay Mechanisms
                                                                • Slide Number 22
                                                                • Fibrin Formation
                                                                • Slide Number 24
                                                                • Fibrinolysis Overview
                                                                • Fibrinolysis Overview
                                                                • Slide Number 27
                                                                • Fibrinolysis Releases D-dimers
                                                                • Basic Pathophysiology of DIC
                                                                • Disseminated Intravascular Coagulation (DIC)
                                                                • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                • Clinical Conditions Associated With DIC
                                                                • Frequency of DIC in Selected Disease States
                                                                • Underlying Diseases in DIC Patients
                                                                • Slide Number 36
                                                                • Slide Number 37
                                                                • Slide Number 38
                                                                • Slide Number 39
                                                                • Pathophysiology of DIC
                                                                • Pathogenesis of DIC in Sepsis
                                                                • Host Response in Severe Sepsis
                                                                • Organ Failure in Severe Sepsis
                                                                • Mechanism of DIC in Organ Failure
                                                                • Interaction of Inflammation and Coagulation in Sepsis
                                                                • Slide Number 47
                                                                • Diverse and Opposing Effects of Thrombin
                                                                • Coagulation and Fibrinolysis in DIC
                                                                • Mechanism of DIC
                                                                • Pathophysiology of DIC
                                                                • Pathophysiology of DIC - Mechanism
                                                                • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                • Pathophysiology of Overt DIC
                                                                • Physiopathology of DIC ndash Overt DIC Findings
                                                                • Slide Number 57
                                                                • Slide Number 58
                                                                • Slide Number 59
                                                                • Slide Number 60
                                                                • Slide Number 61
                                                                • BREAK
                                                                • Diagnostic and Management Approach for DIC
                                                                • Diagnosis of DIC
                                                                • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                • Lab Diagnosis of DIC ndash Screening Tests
                                                                • Slide Number 67
                                                                • Slide Number 68
                                                                • British Journal of Haematology Overt DIC Score
                                                                • Slide Number 70
                                                                • Slide Number 71
                                                                • Slide Number 72
                                                                • Slide Number 73
                                                                • DIC Management Goals
                                                                • DIC Management and Treatment
                                                                • DIC Management Strategies
                                                                • Anticoagulant Factor Concentrate Treatment
                                                                • Anticoagulant Factor Concentrate Treatment Trials
                                                                • Markers of Thrombin amp Plasmin Generation in DIC
                                                                • D-dimer FDPs and DIC
                                                                • D-Dimer and FDPs in DIC
                                                                • Follow Up of DIC State of Disease
                                                                • FMD-Dimer in DIC Major Differences
                                                                • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                • Slide Number 85
                                                                • Slide Number 86
                                                                • Comparing an Automated FM vs Manual FSP Test
                                                                • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                • Slide Number 94
                                                                • Slide Number 95
                                                                • Slide Number 96
                                                                • Slide Number 97
                                                                • Slide Number 98
                                                                • Slide Number 99
                                                                • DIC Case Studies
                                                                • Case Study 1 - Presentation
                                                                • Case Study 1 ndash Lab Results
                                                                • Case Study 1 ndash Microscopy
                                                                • Case Study 1 ndash Diagnosis and Therapy
                                                                • Slide Number 105
                                                                • Slide Number 106
                                                                • Slide Number 107
                                                                • Slide Number 108
                                                                • Slide Number 109
                                                                • Slide Number 110
                                                                • Slide Number 111
                                                                • Slide Number 112
                                                                • Slide Number 113
                                                                • Slide Number 114
                                                                • Slide Number 115
                                                                • Slide Number 116
                                                                • Slide Number 117
                                                                • Slide Number 118
                                                                • Slide Number 119
                                                                • Slide Number 120
                                                                • Slide Number 121
                                                                • Slide Number 122
                                                                • Slide Number 123
                                                                • Slide Number 124
                                                                • Slide Number 125
                                                                • DIC Take Home Messages
                                                                • Slide Number 127
                                                                • Slide Number 128

                                                                  Clinical Conditions Associated With DIC

                                                                  Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                  Frequency of DIC in Selected Disease States

                                                                  Disease Frequency

                                                                  Gram-negative sepsis 30-50

                                                                  Severe trauma and systemic inflammation 50-70

                                                                  Metastasized tumors 15

                                                                  Abruptio placentaamniotic fluid embolism 50

                                                                  Severe preeclampsia 7

                                                                  Giant hemangioma 25

                                                                  Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                                                  Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017

                                                                  Underlying Diseases in DIC Patients

                                                                  In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively

                                                                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                  Epidemiology of DIC

                                                                  Impact of DIC Status on Mortality - 1

                                                                  Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8

                                                                  Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC

                                                                  Impact of DIC Status on Mortality - 2

                                                                  Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                                                  Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients

                                                                  Impact of Age on Mortality in DIC Patients

                                                                  Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                                                  Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)

                                                                  Pathophysiology of DIC

                                                                  Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                  Pathogenesis of DIC in Sepsis

                                                                  Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15

                                                                  Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC

                                                                  Host Response in Severe Sepsis

                                                                  Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral

                                                                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                  Organ Failure in Severe Sepsis

                                                                  Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure

                                                                  Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51

                                                                  Mechanism of DIC in Organ Failure

                                                                  Underlying condition(sepsis trauma)

                                                                  Cytokines

                                                                  TF-mediatedactivation of coagulation

                                                                  Depression of inhibitory systems

                                                                  Reducesfibrinolysis

                                                                  Fibrin deposition

                                                                  Organ failure

                                                                  Inadequate fibrin removal

                                                                  Fibrinformation

                                                                  Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )

                                                                  Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705

                                                                  Interaction of Inflammation and Coagulation in Sepsis

                                                                  Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines

                                                                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                  Mechanism of Multiple Organ Failure in DIC

                                                                  Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

                                                                  Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

                                                                  lipopolysaccharides

                                                                  cytokines

                                                                  coagulation activation

                                                                  mononuclear cell

                                                                  tissue factor

                                                                  Diverse and Opposing Effects of Thrombin

                                                                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                  Coagulation and Fibrinolysis in DIC

                                                                  Soluble fibrin Polymer

                                                                  XIIIa

                                                                  D-Dimer

                                                                  E

                                                                  Fibrin clot

                                                                  Fibrin Degradation Products

                                                                  Fibrinogen Thrombin

                                                                  Fibrinogen Degradation

                                                                  Products

                                                                  D E

                                                                  Plasmin

                                                                  DFM + fibrinopeptides

                                                                  Soluble FM ComplexesPre-throm

                                                                  boticPost-throm

                                                                  botic

                                                                  Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

                                                                  Mechanism of DIC

                                                                  THROMBOSIS

                                                                  Fibrin

                                                                  Blood activationEndothelial lysisTF expression

                                                                  BLEEDING

                                                                  FDPs

                                                                  D-Dimer

                                                                  Plasmin

                                                                  Pathophysiology of DIC

                                                                  1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

                                                                  thromboplastin influx of activated cells (monocytes macrophages)

                                                                  Results in an intravascular deposition of fibrin

                                                                  Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

                                                                  Second step Consumption and depletion of coagulation factors inhibitors (Protein C

                                                                  Protein S AT) and platelets Local fibrinolytic response

                                                                  bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

                                                                  FDP and D-Dimer

                                                                  Bleeding

                                                                  Pathophysiology of DIC - Mechanism

                                                                  Systemic activation of coagulation

                                                                  Intravasculardepositionof fibrin

                                                                  Thrombosis of small and midsize vessels

                                                                  and organ failure

                                                                  Depletion of platelets and

                                                                  coagulation factors

                                                                  Bleeding

                                                                  Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                                                  Pathophysiology of DIC ndash 2 Types of Clinical pictures

                                                                  Chronic = non - overt DICMay be unrecognized clinically

                                                                  Acute = overt DIClife threatening bleedingor multiple organ failure

                                                                  Sub-Acute and Non-Overt DIC Clinical Findings

                                                                  Compensated non-overt DIC Steady low level or intermittent activation

                                                                  bull Compensated by increased production of coagulation components and platelets

                                                                  Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                                                                  Risk of decompensation leading to overt DIC

                                                                  Pathophysiology of Overt DIC

                                                                  Massive activation of coagulation and fibrinolysis

                                                                  Does not allow for compensatory efforts

                                                                  Rapid depletion of coagulation factors inhibitors and platelets

                                                                  Thrombosis multiple organ failures

                                                                  Bleeding complications and shock

                                                                  Physiopathology of DIC ndash Overt DIC Findings

                                                                  Thrombin generation

                                                                  Thrombosis

                                                                  Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                                                                  Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                                                                  Plasmin generationHemorrhage

                                                                  bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                                                                  bull Tachycardia hypotension edema

                                                                  Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                  Pathogenesis Pathways in DIC

                                                                  Cytokines

                                                                  TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                                                                  fibrin inadequateformation fibrin removal

                                                                  Fibrin deposition

                                                                  Inflammation

                                                                  Coagulation

                                                                  Stago Celebrates Lab Week 2017

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                                                                  wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                                                                  wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                                                                  Stago Educational Apps

                                                                  HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                                                                  iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                                                                  BREAK

                                                                  Diagnostic and Management Approach for DIC

                                                                  Diagnosis of DIC

                                                                  Clinical diagnosis is obvious in cases of overt DIC

                                                                  Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                                                  Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                                                  Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                                                  Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                                                  Important to recognize simultaneous formation of thrombin and plasmin

                                                                  Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                  Lab Diagnosis of DIC ndash Screening Tests

                                                                  Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                  Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                                                  fibrinogen level) repeat testing assesses progression

                                                                  Screening tests not clinically specific or sensitive for DIC

                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                  Laboratory Changes in Overt DIC

                                                                  DIC Diagnostic Practices Over Time

                                                                  Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                  British Journal of Haematology Overt DIC Score

                                                                  Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                  ISTH Step by Step DIC Algorithm

                                                                  Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                                  US Based Validation of ISTH DIC Score

                                                                  When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                  Differential Diagnosis in DIC

                                                                  aHUS atypical hemolytic uremic syndrome

                                                                  HUS hemolytic uremic syndrome

                                                                  HIT heparin-induced thrombocytopenia

                                                                  ITP immune thrombocytopenic purpura

                                                                  TTP thrombotic thrombocytopenic purpura

                                                                  DIC and MAHA

                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                  lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                                  When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                                  DIC Management Goals

                                                                  Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                  Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                                  DIC Management and Treatment

                                                                  Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                  Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                                  requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                                  Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                                  DIC Management Strategies

                                                                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                  Anticoagulant Factor Concentrate Treatment

                                                                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                  Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                  Anticoagulant Factor Concentrate Treatment Trials

                                                                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                  Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                  Markers of Thrombin amp Plasmin Generation in DIC

                                                                  D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                  Cut-off value

                                                                  Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                  degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                  D-dimer FDPs and DIC

                                                                  D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                  Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                  Follow Up of DIC State of Disease

                                                                  Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                  Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                  FMD-Dimer in DIC Major Differences

                                                                  onset of thrombosis

                                                                  days

                                                                  Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                  FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                  D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                  of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                  0

                                                                  20

                                                                  40

                                                                  60

                                                                  80

                                                                  100

                                                                  94 85 90N = 62

                                                                  Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                  Positivity of Test Results ISTH Score and Disease State

                                                                  Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                  Red bar positive for 2 points of DIC score

                                                                  Pink bar positive for 1-2 points of DIC score

                                                                  HT hematopoietic tumor

                                                                  IF infection

                                                                  SC solid cancer

                                                                  Markers in Patients with or without DIC

                                                                  Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                  HT hematopoietic tumorIF infectionSC solid cancer

                                                                  Comparing an Automated FM vs Manual FSP Test

                                                                  Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                  Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                  Automated (Mitsubishi) vs Automated (Stago)

                                                                  In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                  Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                  In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                  In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                  In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                  Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                  No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                  Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                  Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                  Non Overt DIC Overt DIC

                                                                  AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                  Trends in Markers of DIC for Different Patients

                                                                  Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                  Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                  Trends in Markers of DIC for Different Patients

                                                                  Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                  FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                  28 day outcome survival

                                                                  28 day outcome death

                                                                  Determination of Cutoffs of FM and D-dimer in DIC

                                                                  Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                  Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                  Determination of Cutoffs of FM and D-dimer in DIC

                                                                  Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                  Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                  DIC Case Studies

                                                                  Case Study 1 - Presentation

                                                                  18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                  Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                  WBC count 77 KμL 423 ndash 907 x KμL

                                                                  RBC count 17 MμL 137 ndash 175 x MμL

                                                                  Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                  Hematocrit 195 401 ndash 510

                                                                  MCV 95 fL 790 ndash 922 fL

                                                                  MPV 12 fL 94 ndash 124 fL

                                                                  Platelet count 9 KμL 161 ndash 347 KμL

                                                                  Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                  Lymphocytes monocytes eosinophils basophils all below normal range

                                                                  PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                  APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                  Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                  D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                  Case Study 1 ndash Microscopy

                                                                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                  Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                  Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                  DIC due to TF release by APL blasts

                                                                  Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                  Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                  20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                  Case Study 2 ndash Presentation

                                                                  TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                  PT 30 sec 113 ndash 146 sec

                                                                  APTT 75 sec 25 ndash 34 sec

                                                                  D-dimer 078 microgml FEU lt050 microgml FEU

                                                                  Fibrinogen 92 mgdl 150-400 mgdl

                                                                  pH 728 738 to 742

                                                                  PaO2 570 mmHg 80-100 mmHg

                                                                  WBC 33 times 103mm3 40-11 times 103mm3

                                                                  ALT 111 IUL 0ndash34 IUL

                                                                  AST 61 IUL 0ndash34 IUL

                                                                  BUN 303 mgdL 08-13 mgdL

                                                                  Case Study 2 ndash Lab Results

                                                                  Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                  Case Study 2 ndash Diagnosis

                                                                  60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                  Case Study 3 ndash Presentation

                                                                  TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                  PT 228 sec 113 ndash 146 sec

                                                                  APTT 45 sec 25 ndash 34 sec

                                                                  D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                  Fibrinogen 82 mgdL 150-400 mgdL

                                                                  FV Normal 70-120

                                                                  FVII Normal 55-170

                                                                  FVIII Normal 60-150

                                                                  Protein C Normal 70-130

                                                                  Hb 134 gdL 14-16 gdL

                                                                  WBC 81 times 103mm3 40-11 times 103mm3

                                                                  ALT 32 IUL 0ndash34 IUL

                                                                  AST 28 IUL 0ndash34 IUL

                                                                  BUN 09 mgdL 08-13 mgdL

                                                                  Case Study 3 ndash Lab Results

                                                                  Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                  Case Study 3 ndash Diagnosis and Therapy

                                                                  Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                  Case Study 4 ndash Presentation

                                                                  TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                  PT 28 sec 113 ndash 146 sec

                                                                  APTT 71 sec 25 ndash 34 sec

                                                                  D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                  Fibrinogen 92 mgdL 150-400 mgdl

                                                                  FV Normal 70-120

                                                                  FVII Normal 55-170

                                                                  FVIII Normal 60-150

                                                                  Protein C Normal 70-130

                                                                  Hb 158 gdL 14-16 gdL

                                                                  WBC 71 times 103mm3 40-11 times 103mm3

                                                                  ALT 60 IUL 0ndash34 IUL

                                                                  AST 47 IUL 0ndash34 IUL

                                                                  BUN 38 mgdL 08-13 mgdL

                                                                  Case Study 4 ndash Lab Results

                                                                  Lyme disease with DICProvide antibiotics with supportive measures

                                                                  Case Study 4 ndash Diagnosis

                                                                  55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                  Case Study 5 ndash Presentation

                                                                  Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                  Case Study 5 ndash Lab Results and Time Course

                                                                  Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                  TEST RESULT REFERENCE RANGE

                                                                  Platelet count 33 x 109L 150-450 x 109L

                                                                  PT 215 sec 103 ndash 128 sec

                                                                  APTT 44 sec 26 ndash 36 sec

                                                                  D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                  Fibrinogen 34 mgdL 200-375 mgdl

                                                                  FII FV FVIII Low Not reported (NR)

                                                                  FVII FIX FX vWF Normal NR

                                                                  Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                  DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                  dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                  (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                  (D) Illustration demonstrating repair

                                                                  Case Study 5 ndash Diagnosis and Treatment

                                                                  Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                  29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                  Case Study 6 ndash Presentation

                                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                  Case Study 6 ndash Lab Results

                                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                  TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                  PT 63 sec gt control 113 ndash 146 sec

                                                                  INR 658 1 ndash 125

                                                                  APTT 80 sec gt control 25 ndash 34 sec

                                                                  D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                  Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                  Albumin 28 gdL NR

                                                                  Hb 58 gdL NR

                                                                  LDH 1196 UL NR

                                                                  SGPT 144 IU NR

                                                                  SGOT 88 IU NR

                                                                  Bilirubin 32 mgdL NR

                                                                  DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                  day postop

                                                                  Case Study 6 ndash Diagnosis and Treatment

                                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                  HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                  Case Study 6 ndash Discussion

                                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                  44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                  Case Study 7 ndash Presentation

                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                  On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                  Case Study 7 ndash Presentation

                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                  Case Study 7 ndash Lab Results vs Time

                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                  Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                  Case Study 7 ndash Diagnosis and Treatment

                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                  On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                  Case Study 7 ndash Diagnosis and Treatment

                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                  DIC Take Home Messages

                                                                  Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                  Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                  DIC

                                                                  Thank you Questions

                                                                  • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                  • Learning Objectives
                                                                  • Slide Number 3
                                                                  • Slide Number 4
                                                                  • Slide Number 5
                                                                  • Slide Number 6
                                                                  • Slide Number 7
                                                                  • Slide Number 8
                                                                  • Wound Sealing
                                                                  • The Three Steps of Hemostasis
                                                                  • Vessel Wall
                                                                  • Slide Number 12
                                                                  • Slide Number 13
                                                                  • Platelet Structure UnactivatedActivated
                                                                  • Primary Hemostasis
                                                                  • Primary Hemostasis Assays
                                                                  • Slide Number 17
                                                                  • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                  • Slide Number 19
                                                                  • Coagulation factors
                                                                  • Coagulation Assay Mechanisms
                                                                  • Slide Number 22
                                                                  • Fibrin Formation
                                                                  • Slide Number 24
                                                                  • Fibrinolysis Overview
                                                                  • Fibrinolysis Overview
                                                                  • Slide Number 27
                                                                  • Fibrinolysis Releases D-dimers
                                                                  • Basic Pathophysiology of DIC
                                                                  • Disseminated Intravascular Coagulation (DIC)
                                                                  • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                  • Clinical Conditions Associated With DIC
                                                                  • Frequency of DIC in Selected Disease States
                                                                  • Underlying Diseases in DIC Patients
                                                                  • Slide Number 36
                                                                  • Slide Number 37
                                                                  • Slide Number 38
                                                                  • Slide Number 39
                                                                  • Pathophysiology of DIC
                                                                  • Pathogenesis of DIC in Sepsis
                                                                  • Host Response in Severe Sepsis
                                                                  • Organ Failure in Severe Sepsis
                                                                  • Mechanism of DIC in Organ Failure
                                                                  • Interaction of Inflammation and Coagulation in Sepsis
                                                                  • Slide Number 47
                                                                  • Diverse and Opposing Effects of Thrombin
                                                                  • Coagulation and Fibrinolysis in DIC
                                                                  • Mechanism of DIC
                                                                  • Pathophysiology of DIC
                                                                  • Pathophysiology of DIC - Mechanism
                                                                  • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                  • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                  • Pathophysiology of Overt DIC
                                                                  • Physiopathology of DIC ndash Overt DIC Findings
                                                                  • Slide Number 57
                                                                  • Slide Number 58
                                                                  • Slide Number 59
                                                                  • Slide Number 60
                                                                  • Slide Number 61
                                                                  • BREAK
                                                                  • Diagnostic and Management Approach for DIC
                                                                  • Diagnosis of DIC
                                                                  • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                  • Lab Diagnosis of DIC ndash Screening Tests
                                                                  • Slide Number 67
                                                                  • Slide Number 68
                                                                  • British Journal of Haematology Overt DIC Score
                                                                  • Slide Number 70
                                                                  • Slide Number 71
                                                                  • Slide Number 72
                                                                  • Slide Number 73
                                                                  • DIC Management Goals
                                                                  • DIC Management and Treatment
                                                                  • DIC Management Strategies
                                                                  • Anticoagulant Factor Concentrate Treatment
                                                                  • Anticoagulant Factor Concentrate Treatment Trials
                                                                  • Markers of Thrombin amp Plasmin Generation in DIC
                                                                  • D-dimer FDPs and DIC
                                                                  • D-Dimer and FDPs in DIC
                                                                  • Follow Up of DIC State of Disease
                                                                  • FMD-Dimer in DIC Major Differences
                                                                  • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                  • Slide Number 85
                                                                  • Slide Number 86
                                                                  • Comparing an Automated FM vs Manual FSP Test
                                                                  • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                  • Slide Number 94
                                                                  • Slide Number 95
                                                                  • Slide Number 96
                                                                  • Slide Number 97
                                                                  • Slide Number 98
                                                                  • Slide Number 99
                                                                  • DIC Case Studies
                                                                  • Case Study 1 - Presentation
                                                                  • Case Study 1 ndash Lab Results
                                                                  • Case Study 1 ndash Microscopy
                                                                  • Case Study 1 ndash Diagnosis and Therapy
                                                                  • Slide Number 105
                                                                  • Slide Number 106
                                                                  • Slide Number 107
                                                                  • Slide Number 108
                                                                  • Slide Number 109
                                                                  • Slide Number 110
                                                                  • Slide Number 111
                                                                  • Slide Number 112
                                                                  • Slide Number 113
                                                                  • Slide Number 114
                                                                  • Slide Number 115
                                                                  • Slide Number 116
                                                                  • Slide Number 117
                                                                  • Slide Number 118
                                                                  • Slide Number 119
                                                                  • Slide Number 120
                                                                  • Slide Number 121
                                                                  • Slide Number 122
                                                                  • Slide Number 123
                                                                  • Slide Number 124
                                                                  • Slide Number 125
                                                                  • DIC Take Home Messages
                                                                  • Slide Number 127
                                                                  • Slide Number 128

                                                                    Frequency of DIC in Selected Disease States

                                                                    Disease Frequency

                                                                    Gram-negative sepsis 30-50

                                                                    Severe trauma and systemic inflammation 50-70

                                                                    Metastasized tumors 15

                                                                    Abruptio placentaamniotic fluid embolism 50

                                                                    Severe preeclampsia 7

                                                                    Giant hemangioma 25

                                                                    Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                                                    Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017

                                                                    Underlying Diseases in DIC Patients

                                                                    In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively

                                                                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                    Epidemiology of DIC

                                                                    Impact of DIC Status on Mortality - 1

                                                                    Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8

                                                                    Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC

                                                                    Impact of DIC Status on Mortality - 2

                                                                    Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                                                    Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients

                                                                    Impact of Age on Mortality in DIC Patients

                                                                    Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                                                    Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)

                                                                    Pathophysiology of DIC

                                                                    Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                    Pathogenesis of DIC in Sepsis

                                                                    Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15

                                                                    Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC

                                                                    Host Response in Severe Sepsis

                                                                    Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral

                                                                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                    Organ Failure in Severe Sepsis

                                                                    Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure

                                                                    Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51

                                                                    Mechanism of DIC in Organ Failure

                                                                    Underlying condition(sepsis trauma)

                                                                    Cytokines

                                                                    TF-mediatedactivation of coagulation

                                                                    Depression of inhibitory systems

                                                                    Reducesfibrinolysis

                                                                    Fibrin deposition

                                                                    Organ failure

                                                                    Inadequate fibrin removal

                                                                    Fibrinformation

                                                                    Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )

                                                                    Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705

                                                                    Interaction of Inflammation and Coagulation in Sepsis

                                                                    Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines

                                                                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                    Mechanism of Multiple Organ Failure in DIC

                                                                    Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

                                                                    Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

                                                                    lipopolysaccharides

                                                                    cytokines

                                                                    coagulation activation

                                                                    mononuclear cell

                                                                    tissue factor

                                                                    Diverse and Opposing Effects of Thrombin

                                                                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                    Coagulation and Fibrinolysis in DIC

                                                                    Soluble fibrin Polymer

                                                                    XIIIa

                                                                    D-Dimer

                                                                    E

                                                                    Fibrin clot

                                                                    Fibrin Degradation Products

                                                                    Fibrinogen Thrombin

                                                                    Fibrinogen Degradation

                                                                    Products

                                                                    D E

                                                                    Plasmin

                                                                    DFM + fibrinopeptides

                                                                    Soluble FM ComplexesPre-throm

                                                                    boticPost-throm

                                                                    botic

                                                                    Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

                                                                    Mechanism of DIC

                                                                    THROMBOSIS

                                                                    Fibrin

                                                                    Blood activationEndothelial lysisTF expression

                                                                    BLEEDING

                                                                    FDPs

                                                                    D-Dimer

                                                                    Plasmin

                                                                    Pathophysiology of DIC

                                                                    1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

                                                                    thromboplastin influx of activated cells (monocytes macrophages)

                                                                    Results in an intravascular deposition of fibrin

                                                                    Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

                                                                    Second step Consumption and depletion of coagulation factors inhibitors (Protein C

                                                                    Protein S AT) and platelets Local fibrinolytic response

                                                                    bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

                                                                    FDP and D-Dimer

                                                                    Bleeding

                                                                    Pathophysiology of DIC - Mechanism

                                                                    Systemic activation of coagulation

                                                                    Intravasculardepositionof fibrin

                                                                    Thrombosis of small and midsize vessels

                                                                    and organ failure

                                                                    Depletion of platelets and

                                                                    coagulation factors

                                                                    Bleeding

                                                                    Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                                                    Pathophysiology of DIC ndash 2 Types of Clinical pictures

                                                                    Chronic = non - overt DICMay be unrecognized clinically

                                                                    Acute = overt DIClife threatening bleedingor multiple organ failure

                                                                    Sub-Acute and Non-Overt DIC Clinical Findings

                                                                    Compensated non-overt DIC Steady low level or intermittent activation

                                                                    bull Compensated by increased production of coagulation components and platelets

                                                                    Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                                                                    Risk of decompensation leading to overt DIC

                                                                    Pathophysiology of Overt DIC

                                                                    Massive activation of coagulation and fibrinolysis

                                                                    Does not allow for compensatory efforts

                                                                    Rapid depletion of coagulation factors inhibitors and platelets

                                                                    Thrombosis multiple organ failures

                                                                    Bleeding complications and shock

                                                                    Physiopathology of DIC ndash Overt DIC Findings

                                                                    Thrombin generation

                                                                    Thrombosis

                                                                    Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                                                                    Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                                                                    Plasmin generationHemorrhage

                                                                    bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                                                                    bull Tachycardia hypotension edema

                                                                    Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                    Pathogenesis Pathways in DIC

                                                                    Cytokines

                                                                    TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                                                                    fibrin inadequateformation fibrin removal

                                                                    Fibrin deposition

                                                                    Inflammation

                                                                    Coagulation

                                                                    Stago Celebrates Lab Week 2017

                                                                    NA

                                                                    Stago 247 Educational Webinar Sites

                                                                    wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                                                                    wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                                                                    Stago Educational Apps

                                                                    HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                                                                    iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                                                                    BREAK

                                                                    Diagnostic and Management Approach for DIC

                                                                    Diagnosis of DIC

                                                                    Clinical diagnosis is obvious in cases of overt DIC

                                                                    Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                                                    Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                                                    Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                                                    Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                                                    Important to recognize simultaneous formation of thrombin and plasmin

                                                                    Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                    Lab Diagnosis of DIC ndash Screening Tests

                                                                    Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                    Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                                                    fibrinogen level) repeat testing assesses progression

                                                                    Screening tests not clinically specific or sensitive for DIC

                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                    Laboratory Changes in Overt DIC

                                                                    DIC Diagnostic Practices Over Time

                                                                    Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                    British Journal of Haematology Overt DIC Score

                                                                    Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                    ISTH Step by Step DIC Algorithm

                                                                    Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                                    US Based Validation of ISTH DIC Score

                                                                    When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                    Differential Diagnosis in DIC

                                                                    aHUS atypical hemolytic uremic syndrome

                                                                    HUS hemolytic uremic syndrome

                                                                    HIT heparin-induced thrombocytopenia

                                                                    ITP immune thrombocytopenic purpura

                                                                    TTP thrombotic thrombocytopenic purpura

                                                                    DIC and MAHA

                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                    lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                                    When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                                    DIC Management Goals

                                                                    Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                    Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                                    DIC Management and Treatment

                                                                    Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                    Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                                    requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                                    Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                                    DIC Management Strategies

                                                                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                    Anticoagulant Factor Concentrate Treatment

                                                                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                    Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                    Anticoagulant Factor Concentrate Treatment Trials

                                                                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                    Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                    Markers of Thrombin amp Plasmin Generation in DIC

                                                                    D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                    Cut-off value

                                                                    Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                    degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                    D-dimer FDPs and DIC

                                                                    D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                    Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                    Follow Up of DIC State of Disease

                                                                    Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                    Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                    FMD-Dimer in DIC Major Differences

                                                                    onset of thrombosis

                                                                    days

                                                                    Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                    FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                    D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                    of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                    0

                                                                    20

                                                                    40

                                                                    60

                                                                    80

                                                                    100

                                                                    94 85 90N = 62

                                                                    Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                    Positivity of Test Results ISTH Score and Disease State

                                                                    Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                    Red bar positive for 2 points of DIC score

                                                                    Pink bar positive for 1-2 points of DIC score

                                                                    HT hematopoietic tumor

                                                                    IF infection

                                                                    SC solid cancer

                                                                    Markers in Patients with or without DIC

                                                                    Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                    HT hematopoietic tumorIF infectionSC solid cancer

                                                                    Comparing an Automated FM vs Manual FSP Test

                                                                    Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                    Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                    Automated (Mitsubishi) vs Automated (Stago)

                                                                    In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                    Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                    In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                    In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                    In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                    Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                    No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                    Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                    Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                    Non Overt DIC Overt DIC

                                                                    AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                    Trends in Markers of DIC for Different Patients

                                                                    Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                    Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                    Trends in Markers of DIC for Different Patients

                                                                    Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                    FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                    28 day outcome survival

                                                                    28 day outcome death

                                                                    Determination of Cutoffs of FM and D-dimer in DIC

                                                                    Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                    Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                    Determination of Cutoffs of FM and D-dimer in DIC

                                                                    Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                    Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                    DIC Case Studies

                                                                    Case Study 1 - Presentation

                                                                    18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                    Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                    WBC count 77 KμL 423 ndash 907 x KμL

                                                                    RBC count 17 MμL 137 ndash 175 x MμL

                                                                    Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                    Hematocrit 195 401 ndash 510

                                                                    MCV 95 fL 790 ndash 922 fL

                                                                    MPV 12 fL 94 ndash 124 fL

                                                                    Platelet count 9 KμL 161 ndash 347 KμL

                                                                    Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                    Lymphocytes monocytes eosinophils basophils all below normal range

                                                                    PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                    APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                    Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                    D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                    Case Study 1 ndash Microscopy

                                                                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                    Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                    Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                    DIC due to TF release by APL blasts

                                                                    Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                    Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                    20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                    Case Study 2 ndash Presentation

                                                                    TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                    PT 30 sec 113 ndash 146 sec

                                                                    APTT 75 sec 25 ndash 34 sec

                                                                    D-dimer 078 microgml FEU lt050 microgml FEU

                                                                    Fibrinogen 92 mgdl 150-400 mgdl

                                                                    pH 728 738 to 742

                                                                    PaO2 570 mmHg 80-100 mmHg

                                                                    WBC 33 times 103mm3 40-11 times 103mm3

                                                                    ALT 111 IUL 0ndash34 IUL

                                                                    AST 61 IUL 0ndash34 IUL

                                                                    BUN 303 mgdL 08-13 mgdL

                                                                    Case Study 2 ndash Lab Results

                                                                    Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                    Case Study 2 ndash Diagnosis

                                                                    60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                    Case Study 3 ndash Presentation

                                                                    TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                    PT 228 sec 113 ndash 146 sec

                                                                    APTT 45 sec 25 ndash 34 sec

                                                                    D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                    Fibrinogen 82 mgdL 150-400 mgdL

                                                                    FV Normal 70-120

                                                                    FVII Normal 55-170

                                                                    FVIII Normal 60-150

                                                                    Protein C Normal 70-130

                                                                    Hb 134 gdL 14-16 gdL

                                                                    WBC 81 times 103mm3 40-11 times 103mm3

                                                                    ALT 32 IUL 0ndash34 IUL

                                                                    AST 28 IUL 0ndash34 IUL

                                                                    BUN 09 mgdL 08-13 mgdL

                                                                    Case Study 3 ndash Lab Results

                                                                    Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                    Case Study 3 ndash Diagnosis and Therapy

                                                                    Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                    Case Study 4 ndash Presentation

                                                                    TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                    PT 28 sec 113 ndash 146 sec

                                                                    APTT 71 sec 25 ndash 34 sec

                                                                    D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                    Fibrinogen 92 mgdL 150-400 mgdl

                                                                    FV Normal 70-120

                                                                    FVII Normal 55-170

                                                                    FVIII Normal 60-150

                                                                    Protein C Normal 70-130

                                                                    Hb 158 gdL 14-16 gdL

                                                                    WBC 71 times 103mm3 40-11 times 103mm3

                                                                    ALT 60 IUL 0ndash34 IUL

                                                                    AST 47 IUL 0ndash34 IUL

                                                                    BUN 38 mgdL 08-13 mgdL

                                                                    Case Study 4 ndash Lab Results

                                                                    Lyme disease with DICProvide antibiotics with supportive measures

                                                                    Case Study 4 ndash Diagnosis

                                                                    55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                    Case Study 5 ndash Presentation

                                                                    Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                    Case Study 5 ndash Lab Results and Time Course

                                                                    Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                    TEST RESULT REFERENCE RANGE

                                                                    Platelet count 33 x 109L 150-450 x 109L

                                                                    PT 215 sec 103 ndash 128 sec

                                                                    APTT 44 sec 26 ndash 36 sec

                                                                    D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                    Fibrinogen 34 mgdL 200-375 mgdl

                                                                    FII FV FVIII Low Not reported (NR)

                                                                    FVII FIX FX vWF Normal NR

                                                                    Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                    DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                    dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                    (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                    (D) Illustration demonstrating repair

                                                                    Case Study 5 ndash Diagnosis and Treatment

                                                                    Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                    29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                    Case Study 6 ndash Presentation

                                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                    Case Study 6 ndash Lab Results

                                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                    TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                    PT 63 sec gt control 113 ndash 146 sec

                                                                    INR 658 1 ndash 125

                                                                    APTT 80 sec gt control 25 ndash 34 sec

                                                                    D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                    Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                    Albumin 28 gdL NR

                                                                    Hb 58 gdL NR

                                                                    LDH 1196 UL NR

                                                                    SGPT 144 IU NR

                                                                    SGOT 88 IU NR

                                                                    Bilirubin 32 mgdL NR

                                                                    DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                    day postop

                                                                    Case Study 6 ndash Diagnosis and Treatment

                                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                    HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                    Case Study 6 ndash Discussion

                                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                    44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                    Case Study 7 ndash Presentation

                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                    On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                    Case Study 7 ndash Presentation

                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                    Case Study 7 ndash Lab Results vs Time

                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                    Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                    Case Study 7 ndash Diagnosis and Treatment

                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                    On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                    Case Study 7 ndash Diagnosis and Treatment

                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                    DIC Take Home Messages

                                                                    Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                    Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                    DIC

                                                                    Thank you Questions

                                                                    • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                    • Learning Objectives
                                                                    • Slide Number 3
                                                                    • Slide Number 4
                                                                    • Slide Number 5
                                                                    • Slide Number 6
                                                                    • Slide Number 7
                                                                    • Slide Number 8
                                                                    • Wound Sealing
                                                                    • The Three Steps of Hemostasis
                                                                    • Vessel Wall
                                                                    • Slide Number 12
                                                                    • Slide Number 13
                                                                    • Platelet Structure UnactivatedActivated
                                                                    • Primary Hemostasis
                                                                    • Primary Hemostasis Assays
                                                                    • Slide Number 17
                                                                    • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                    • Slide Number 19
                                                                    • Coagulation factors
                                                                    • Coagulation Assay Mechanisms
                                                                    • Slide Number 22
                                                                    • Fibrin Formation
                                                                    • Slide Number 24
                                                                    • Fibrinolysis Overview
                                                                    • Fibrinolysis Overview
                                                                    • Slide Number 27
                                                                    • Fibrinolysis Releases D-dimers
                                                                    • Basic Pathophysiology of DIC
                                                                    • Disseminated Intravascular Coagulation (DIC)
                                                                    • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                    • Clinical Conditions Associated With DIC
                                                                    • Frequency of DIC in Selected Disease States
                                                                    • Underlying Diseases in DIC Patients
                                                                    • Slide Number 36
                                                                    • Slide Number 37
                                                                    • Slide Number 38
                                                                    • Slide Number 39
                                                                    • Pathophysiology of DIC
                                                                    • Pathogenesis of DIC in Sepsis
                                                                    • Host Response in Severe Sepsis
                                                                    • Organ Failure in Severe Sepsis
                                                                    • Mechanism of DIC in Organ Failure
                                                                    • Interaction of Inflammation and Coagulation in Sepsis
                                                                    • Slide Number 47
                                                                    • Diverse and Opposing Effects of Thrombin
                                                                    • Coagulation and Fibrinolysis in DIC
                                                                    • Mechanism of DIC
                                                                    • Pathophysiology of DIC
                                                                    • Pathophysiology of DIC - Mechanism
                                                                    • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                    • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                    • Pathophysiology of Overt DIC
                                                                    • Physiopathology of DIC ndash Overt DIC Findings
                                                                    • Slide Number 57
                                                                    • Slide Number 58
                                                                    • Slide Number 59
                                                                    • Slide Number 60
                                                                    • Slide Number 61
                                                                    • BREAK
                                                                    • Diagnostic and Management Approach for DIC
                                                                    • Diagnosis of DIC
                                                                    • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                    • Lab Diagnosis of DIC ndash Screening Tests
                                                                    • Slide Number 67
                                                                    • Slide Number 68
                                                                    • British Journal of Haematology Overt DIC Score
                                                                    • Slide Number 70
                                                                    • Slide Number 71
                                                                    • Slide Number 72
                                                                    • Slide Number 73
                                                                    • DIC Management Goals
                                                                    • DIC Management and Treatment
                                                                    • DIC Management Strategies
                                                                    • Anticoagulant Factor Concentrate Treatment
                                                                    • Anticoagulant Factor Concentrate Treatment Trials
                                                                    • Markers of Thrombin amp Plasmin Generation in DIC
                                                                    • D-dimer FDPs and DIC
                                                                    • D-Dimer and FDPs in DIC
                                                                    • Follow Up of DIC State of Disease
                                                                    • FMD-Dimer in DIC Major Differences
                                                                    • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                    • Slide Number 85
                                                                    • Slide Number 86
                                                                    • Comparing an Automated FM vs Manual FSP Test
                                                                    • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                    • Slide Number 94
                                                                    • Slide Number 95
                                                                    • Slide Number 96
                                                                    • Slide Number 97
                                                                    • Slide Number 98
                                                                    • Slide Number 99
                                                                    • DIC Case Studies
                                                                    • Case Study 1 - Presentation
                                                                    • Case Study 1 ndash Lab Results
                                                                    • Case Study 1 ndash Microscopy
                                                                    • Case Study 1 ndash Diagnosis and Therapy
                                                                    • Slide Number 105
                                                                    • Slide Number 106
                                                                    • Slide Number 107
                                                                    • Slide Number 108
                                                                    • Slide Number 109
                                                                    • Slide Number 110
                                                                    • Slide Number 111
                                                                    • Slide Number 112
                                                                    • Slide Number 113
                                                                    • Slide Number 114
                                                                    • Slide Number 115
                                                                    • Slide Number 116
                                                                    • Slide Number 117
                                                                    • Slide Number 118
                                                                    • Slide Number 119
                                                                    • Slide Number 120
                                                                    • Slide Number 121
                                                                    • Slide Number 122
                                                                    • Slide Number 123
                                                                    • Slide Number 124
                                                                    • Slide Number 125
                                                                    • DIC Take Home Messages
                                                                    • Slide Number 127
                                                                    • Slide Number 128

                                                                      Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017

                                                                      Underlying Diseases in DIC Patients

                                                                      In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively

                                                                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                      Epidemiology of DIC

                                                                      Impact of DIC Status on Mortality - 1

                                                                      Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8

                                                                      Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC

                                                                      Impact of DIC Status on Mortality - 2

                                                                      Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                                                      Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients

                                                                      Impact of Age on Mortality in DIC Patients

                                                                      Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                                                      Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)

                                                                      Pathophysiology of DIC

                                                                      Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                      Pathogenesis of DIC in Sepsis

                                                                      Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15

                                                                      Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC

                                                                      Host Response in Severe Sepsis

                                                                      Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral

                                                                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                      Organ Failure in Severe Sepsis

                                                                      Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure

                                                                      Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51

                                                                      Mechanism of DIC in Organ Failure

                                                                      Underlying condition(sepsis trauma)

                                                                      Cytokines

                                                                      TF-mediatedactivation of coagulation

                                                                      Depression of inhibitory systems

                                                                      Reducesfibrinolysis

                                                                      Fibrin deposition

                                                                      Organ failure

                                                                      Inadequate fibrin removal

                                                                      Fibrinformation

                                                                      Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )

                                                                      Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705

                                                                      Interaction of Inflammation and Coagulation in Sepsis

                                                                      Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines

                                                                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                      Mechanism of Multiple Organ Failure in DIC

                                                                      Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

                                                                      Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

                                                                      lipopolysaccharides

                                                                      cytokines

                                                                      coagulation activation

                                                                      mononuclear cell

                                                                      tissue factor

                                                                      Diverse and Opposing Effects of Thrombin

                                                                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                      Coagulation and Fibrinolysis in DIC

                                                                      Soluble fibrin Polymer

                                                                      XIIIa

                                                                      D-Dimer

                                                                      E

                                                                      Fibrin clot

                                                                      Fibrin Degradation Products

                                                                      Fibrinogen Thrombin

                                                                      Fibrinogen Degradation

                                                                      Products

                                                                      D E

                                                                      Plasmin

                                                                      DFM + fibrinopeptides

                                                                      Soluble FM ComplexesPre-throm

                                                                      boticPost-throm

                                                                      botic

                                                                      Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

                                                                      Mechanism of DIC

                                                                      THROMBOSIS

                                                                      Fibrin

                                                                      Blood activationEndothelial lysisTF expression

                                                                      BLEEDING

                                                                      FDPs

                                                                      D-Dimer

                                                                      Plasmin

                                                                      Pathophysiology of DIC

                                                                      1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

                                                                      thromboplastin influx of activated cells (monocytes macrophages)

                                                                      Results in an intravascular deposition of fibrin

                                                                      Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

                                                                      Second step Consumption and depletion of coagulation factors inhibitors (Protein C

                                                                      Protein S AT) and platelets Local fibrinolytic response

                                                                      bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

                                                                      FDP and D-Dimer

                                                                      Bleeding

                                                                      Pathophysiology of DIC - Mechanism

                                                                      Systemic activation of coagulation

                                                                      Intravasculardepositionof fibrin

                                                                      Thrombosis of small and midsize vessels

                                                                      and organ failure

                                                                      Depletion of platelets and

                                                                      coagulation factors

                                                                      Bleeding

                                                                      Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                                                      Pathophysiology of DIC ndash 2 Types of Clinical pictures

                                                                      Chronic = non - overt DICMay be unrecognized clinically

                                                                      Acute = overt DIClife threatening bleedingor multiple organ failure

                                                                      Sub-Acute and Non-Overt DIC Clinical Findings

                                                                      Compensated non-overt DIC Steady low level or intermittent activation

                                                                      bull Compensated by increased production of coagulation components and platelets

                                                                      Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                                                                      Risk of decompensation leading to overt DIC

                                                                      Pathophysiology of Overt DIC

                                                                      Massive activation of coagulation and fibrinolysis

                                                                      Does not allow for compensatory efforts

                                                                      Rapid depletion of coagulation factors inhibitors and platelets

                                                                      Thrombosis multiple organ failures

                                                                      Bleeding complications and shock

                                                                      Physiopathology of DIC ndash Overt DIC Findings

                                                                      Thrombin generation

                                                                      Thrombosis

                                                                      Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                                                                      Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                                                                      Plasmin generationHemorrhage

                                                                      bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                                                                      bull Tachycardia hypotension edema

                                                                      Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                      Pathogenesis Pathways in DIC

                                                                      Cytokines

                                                                      TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                                                                      fibrin inadequateformation fibrin removal

                                                                      Fibrin deposition

                                                                      Inflammation

                                                                      Coagulation

                                                                      Stago Celebrates Lab Week 2017

                                                                      NA

                                                                      Stago 247 Educational Webinar Sites

                                                                      wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                                                                      wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                                                                      Stago Educational Apps

                                                                      HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                                                                      iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                                                                      BREAK

                                                                      Diagnostic and Management Approach for DIC

                                                                      Diagnosis of DIC

                                                                      Clinical diagnosis is obvious in cases of overt DIC

                                                                      Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                                                      Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                                                      Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                                                      Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                                                      Important to recognize simultaneous formation of thrombin and plasmin

                                                                      Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                      Lab Diagnosis of DIC ndash Screening Tests

                                                                      Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                      Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                                                      fibrinogen level) repeat testing assesses progression

                                                                      Screening tests not clinically specific or sensitive for DIC

                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                      Laboratory Changes in Overt DIC

                                                                      DIC Diagnostic Practices Over Time

                                                                      Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                      British Journal of Haematology Overt DIC Score

                                                                      Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                      ISTH Step by Step DIC Algorithm

                                                                      Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                                      US Based Validation of ISTH DIC Score

                                                                      When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                      Differential Diagnosis in DIC

                                                                      aHUS atypical hemolytic uremic syndrome

                                                                      HUS hemolytic uremic syndrome

                                                                      HIT heparin-induced thrombocytopenia

                                                                      ITP immune thrombocytopenic purpura

                                                                      TTP thrombotic thrombocytopenic purpura

                                                                      DIC and MAHA

                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                      lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                                      When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                                      DIC Management Goals

                                                                      Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                      Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                                      DIC Management and Treatment

                                                                      Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                      Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                                      requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                                      Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                                      DIC Management Strategies

                                                                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                      Anticoagulant Factor Concentrate Treatment

                                                                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                      Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                      Anticoagulant Factor Concentrate Treatment Trials

                                                                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                      Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                      Markers of Thrombin amp Plasmin Generation in DIC

                                                                      D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                      Cut-off value

                                                                      Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                      degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                      D-dimer FDPs and DIC

                                                                      D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                      Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                      Follow Up of DIC State of Disease

                                                                      Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                      Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                      FMD-Dimer in DIC Major Differences

                                                                      onset of thrombosis

                                                                      days

                                                                      Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                      FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                      D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                      of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                      0

                                                                      20

                                                                      40

                                                                      60

                                                                      80

                                                                      100

                                                                      94 85 90N = 62

                                                                      Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                      Positivity of Test Results ISTH Score and Disease State

                                                                      Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                      Red bar positive for 2 points of DIC score

                                                                      Pink bar positive for 1-2 points of DIC score

                                                                      HT hematopoietic tumor

                                                                      IF infection

                                                                      SC solid cancer

                                                                      Markers in Patients with or without DIC

                                                                      Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                      HT hematopoietic tumorIF infectionSC solid cancer

                                                                      Comparing an Automated FM vs Manual FSP Test

                                                                      Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                      Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                      Automated (Mitsubishi) vs Automated (Stago)

                                                                      In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                      Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                      In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                      In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                      In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                      Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                      No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                      Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                      Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                      Non Overt DIC Overt DIC

                                                                      AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                      Trends in Markers of DIC for Different Patients

                                                                      Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                      Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                      Trends in Markers of DIC for Different Patients

                                                                      Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                      FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                      28 day outcome survival

                                                                      28 day outcome death

                                                                      Determination of Cutoffs of FM and D-dimer in DIC

                                                                      Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                      Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                      Determination of Cutoffs of FM and D-dimer in DIC

                                                                      Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                      Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                      DIC Case Studies

                                                                      Case Study 1 - Presentation

                                                                      18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                      Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                      WBC count 77 KμL 423 ndash 907 x KμL

                                                                      RBC count 17 MμL 137 ndash 175 x MμL

                                                                      Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                      Hematocrit 195 401 ndash 510

                                                                      MCV 95 fL 790 ndash 922 fL

                                                                      MPV 12 fL 94 ndash 124 fL

                                                                      Platelet count 9 KμL 161 ndash 347 KμL

                                                                      Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                      Lymphocytes monocytes eosinophils basophils all below normal range

                                                                      PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                      APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                      Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                      D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                      Case Study 1 ndash Microscopy

                                                                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                      Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                      Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                      DIC due to TF release by APL blasts

                                                                      Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                      Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                      20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                      Case Study 2 ndash Presentation

                                                                      TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                      PT 30 sec 113 ndash 146 sec

                                                                      APTT 75 sec 25 ndash 34 sec

                                                                      D-dimer 078 microgml FEU lt050 microgml FEU

                                                                      Fibrinogen 92 mgdl 150-400 mgdl

                                                                      pH 728 738 to 742

                                                                      PaO2 570 mmHg 80-100 mmHg

                                                                      WBC 33 times 103mm3 40-11 times 103mm3

                                                                      ALT 111 IUL 0ndash34 IUL

                                                                      AST 61 IUL 0ndash34 IUL

                                                                      BUN 303 mgdL 08-13 mgdL

                                                                      Case Study 2 ndash Lab Results

                                                                      Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                      Case Study 2 ndash Diagnosis

                                                                      60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                      Case Study 3 ndash Presentation

                                                                      TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                      PT 228 sec 113 ndash 146 sec

                                                                      APTT 45 sec 25 ndash 34 sec

                                                                      D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                      Fibrinogen 82 mgdL 150-400 mgdL

                                                                      FV Normal 70-120

                                                                      FVII Normal 55-170

                                                                      FVIII Normal 60-150

                                                                      Protein C Normal 70-130

                                                                      Hb 134 gdL 14-16 gdL

                                                                      WBC 81 times 103mm3 40-11 times 103mm3

                                                                      ALT 32 IUL 0ndash34 IUL

                                                                      AST 28 IUL 0ndash34 IUL

                                                                      BUN 09 mgdL 08-13 mgdL

                                                                      Case Study 3 ndash Lab Results

                                                                      Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                      Case Study 3 ndash Diagnosis and Therapy

                                                                      Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                      Case Study 4 ndash Presentation

                                                                      TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                      PT 28 sec 113 ndash 146 sec

                                                                      APTT 71 sec 25 ndash 34 sec

                                                                      D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                      Fibrinogen 92 mgdL 150-400 mgdl

                                                                      FV Normal 70-120

                                                                      FVII Normal 55-170

                                                                      FVIII Normal 60-150

                                                                      Protein C Normal 70-130

                                                                      Hb 158 gdL 14-16 gdL

                                                                      WBC 71 times 103mm3 40-11 times 103mm3

                                                                      ALT 60 IUL 0ndash34 IUL

                                                                      AST 47 IUL 0ndash34 IUL

                                                                      BUN 38 mgdL 08-13 mgdL

                                                                      Case Study 4 ndash Lab Results

                                                                      Lyme disease with DICProvide antibiotics with supportive measures

                                                                      Case Study 4 ndash Diagnosis

                                                                      55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                      Case Study 5 ndash Presentation

                                                                      Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                      Case Study 5 ndash Lab Results and Time Course

                                                                      Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                      TEST RESULT REFERENCE RANGE

                                                                      Platelet count 33 x 109L 150-450 x 109L

                                                                      PT 215 sec 103 ndash 128 sec

                                                                      APTT 44 sec 26 ndash 36 sec

                                                                      D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                      Fibrinogen 34 mgdL 200-375 mgdl

                                                                      FII FV FVIII Low Not reported (NR)

                                                                      FVII FIX FX vWF Normal NR

                                                                      Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                      DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                      dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                      (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                      (D) Illustration demonstrating repair

                                                                      Case Study 5 ndash Diagnosis and Treatment

                                                                      Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                      29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                      Case Study 6 ndash Presentation

                                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                      Case Study 6 ndash Lab Results

                                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                      TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                      PT 63 sec gt control 113 ndash 146 sec

                                                                      INR 658 1 ndash 125

                                                                      APTT 80 sec gt control 25 ndash 34 sec

                                                                      D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                      Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                      Albumin 28 gdL NR

                                                                      Hb 58 gdL NR

                                                                      LDH 1196 UL NR

                                                                      SGPT 144 IU NR

                                                                      SGOT 88 IU NR

                                                                      Bilirubin 32 mgdL NR

                                                                      DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                      day postop

                                                                      Case Study 6 ndash Diagnosis and Treatment

                                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                      HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                      Case Study 6 ndash Discussion

                                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                      44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                      Case Study 7 ndash Presentation

                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                      On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                      Case Study 7 ndash Presentation

                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                      Case Study 7 ndash Lab Results vs Time

                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                      Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                      Case Study 7 ndash Diagnosis and Treatment

                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                      On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                      Case Study 7 ndash Diagnosis and Treatment

                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                      DIC Take Home Messages

                                                                      Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                      Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                      DIC

                                                                      Thank you Questions

                                                                      • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                      • Learning Objectives
                                                                      • Slide Number 3
                                                                      • Slide Number 4
                                                                      • Slide Number 5
                                                                      • Slide Number 6
                                                                      • Slide Number 7
                                                                      • Slide Number 8
                                                                      • Wound Sealing
                                                                      • The Three Steps of Hemostasis
                                                                      • Vessel Wall
                                                                      • Slide Number 12
                                                                      • Slide Number 13
                                                                      • Platelet Structure UnactivatedActivated
                                                                      • Primary Hemostasis
                                                                      • Primary Hemostasis Assays
                                                                      • Slide Number 17
                                                                      • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                      • Slide Number 19
                                                                      • Coagulation factors
                                                                      • Coagulation Assay Mechanisms
                                                                      • Slide Number 22
                                                                      • Fibrin Formation
                                                                      • Slide Number 24
                                                                      • Fibrinolysis Overview
                                                                      • Fibrinolysis Overview
                                                                      • Slide Number 27
                                                                      • Fibrinolysis Releases D-dimers
                                                                      • Basic Pathophysiology of DIC
                                                                      • Disseminated Intravascular Coagulation (DIC)
                                                                      • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                      • Clinical Conditions Associated With DIC
                                                                      • Frequency of DIC in Selected Disease States
                                                                      • Underlying Diseases in DIC Patients
                                                                      • Slide Number 36
                                                                      • Slide Number 37
                                                                      • Slide Number 38
                                                                      • Slide Number 39
                                                                      • Pathophysiology of DIC
                                                                      • Pathogenesis of DIC in Sepsis
                                                                      • Host Response in Severe Sepsis
                                                                      • Organ Failure in Severe Sepsis
                                                                      • Mechanism of DIC in Organ Failure
                                                                      • Interaction of Inflammation and Coagulation in Sepsis
                                                                      • Slide Number 47
                                                                      • Diverse and Opposing Effects of Thrombin
                                                                      • Coagulation and Fibrinolysis in DIC
                                                                      • Mechanism of DIC
                                                                      • Pathophysiology of DIC
                                                                      • Pathophysiology of DIC - Mechanism
                                                                      • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                      • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                      • Pathophysiology of Overt DIC
                                                                      • Physiopathology of DIC ndash Overt DIC Findings
                                                                      • Slide Number 57
                                                                      • Slide Number 58
                                                                      • Slide Number 59
                                                                      • Slide Number 60
                                                                      • Slide Number 61
                                                                      • BREAK
                                                                      • Diagnostic and Management Approach for DIC
                                                                      • Diagnosis of DIC
                                                                      • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                      • Lab Diagnosis of DIC ndash Screening Tests
                                                                      • Slide Number 67
                                                                      • Slide Number 68
                                                                      • British Journal of Haematology Overt DIC Score
                                                                      • Slide Number 70
                                                                      • Slide Number 71
                                                                      • Slide Number 72
                                                                      • Slide Number 73
                                                                      • DIC Management Goals
                                                                      • DIC Management and Treatment
                                                                      • DIC Management Strategies
                                                                      • Anticoagulant Factor Concentrate Treatment
                                                                      • Anticoagulant Factor Concentrate Treatment Trials
                                                                      • Markers of Thrombin amp Plasmin Generation in DIC
                                                                      • D-dimer FDPs and DIC
                                                                      • D-Dimer and FDPs in DIC
                                                                      • Follow Up of DIC State of Disease
                                                                      • FMD-Dimer in DIC Major Differences
                                                                      • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                      • Slide Number 85
                                                                      • Slide Number 86
                                                                      • Comparing an Automated FM vs Manual FSP Test
                                                                      • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                      • Slide Number 94
                                                                      • Slide Number 95
                                                                      • Slide Number 96
                                                                      • Slide Number 97
                                                                      • Slide Number 98
                                                                      • Slide Number 99
                                                                      • DIC Case Studies
                                                                      • Case Study 1 - Presentation
                                                                      • Case Study 1 ndash Lab Results
                                                                      • Case Study 1 ndash Microscopy
                                                                      • Case Study 1 ndash Diagnosis and Therapy
                                                                      • Slide Number 105
                                                                      • Slide Number 106
                                                                      • Slide Number 107
                                                                      • Slide Number 108
                                                                      • Slide Number 109
                                                                      • Slide Number 110
                                                                      • Slide Number 111
                                                                      • Slide Number 112
                                                                      • Slide Number 113
                                                                      • Slide Number 114
                                                                      • Slide Number 115
                                                                      • Slide Number 116
                                                                      • Slide Number 117
                                                                      • Slide Number 118
                                                                      • Slide Number 119
                                                                      • Slide Number 120
                                                                      • Slide Number 121
                                                                      • Slide Number 122
                                                                      • Slide Number 123
                                                                      • Slide Number 124
                                                                      • Slide Number 125
                                                                      • DIC Take Home Messages
                                                                      • Slide Number 127
                                                                      • Slide Number 128

                                                                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                        Epidemiology of DIC

                                                                        Impact of DIC Status on Mortality - 1

                                                                        Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8

                                                                        Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC

                                                                        Impact of DIC Status on Mortality - 2

                                                                        Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                                                        Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients

                                                                        Impact of Age on Mortality in DIC Patients

                                                                        Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                                                        Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)

                                                                        Pathophysiology of DIC

                                                                        Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                        Pathogenesis of DIC in Sepsis

                                                                        Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15

                                                                        Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC

                                                                        Host Response in Severe Sepsis

                                                                        Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral

                                                                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                        Organ Failure in Severe Sepsis

                                                                        Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure

                                                                        Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51

                                                                        Mechanism of DIC in Organ Failure

                                                                        Underlying condition(sepsis trauma)

                                                                        Cytokines

                                                                        TF-mediatedactivation of coagulation

                                                                        Depression of inhibitory systems

                                                                        Reducesfibrinolysis

                                                                        Fibrin deposition

                                                                        Organ failure

                                                                        Inadequate fibrin removal

                                                                        Fibrinformation

                                                                        Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )

                                                                        Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705

                                                                        Interaction of Inflammation and Coagulation in Sepsis

                                                                        Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines

                                                                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                        Mechanism of Multiple Organ Failure in DIC

                                                                        Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

                                                                        Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

                                                                        lipopolysaccharides

                                                                        cytokines

                                                                        coagulation activation

                                                                        mononuclear cell

                                                                        tissue factor

                                                                        Diverse and Opposing Effects of Thrombin

                                                                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                        Coagulation and Fibrinolysis in DIC

                                                                        Soluble fibrin Polymer

                                                                        XIIIa

                                                                        D-Dimer

                                                                        E

                                                                        Fibrin clot

                                                                        Fibrin Degradation Products

                                                                        Fibrinogen Thrombin

                                                                        Fibrinogen Degradation

                                                                        Products

                                                                        D E

                                                                        Plasmin

                                                                        DFM + fibrinopeptides

                                                                        Soluble FM ComplexesPre-throm

                                                                        boticPost-throm

                                                                        botic

                                                                        Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

                                                                        Mechanism of DIC

                                                                        THROMBOSIS

                                                                        Fibrin

                                                                        Blood activationEndothelial lysisTF expression

                                                                        BLEEDING

                                                                        FDPs

                                                                        D-Dimer

                                                                        Plasmin

                                                                        Pathophysiology of DIC

                                                                        1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

                                                                        thromboplastin influx of activated cells (monocytes macrophages)

                                                                        Results in an intravascular deposition of fibrin

                                                                        Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

                                                                        Second step Consumption and depletion of coagulation factors inhibitors (Protein C

                                                                        Protein S AT) and platelets Local fibrinolytic response

                                                                        bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

                                                                        FDP and D-Dimer

                                                                        Bleeding

                                                                        Pathophysiology of DIC - Mechanism

                                                                        Systemic activation of coagulation

                                                                        Intravasculardepositionof fibrin

                                                                        Thrombosis of small and midsize vessels

                                                                        and organ failure

                                                                        Depletion of platelets and

                                                                        coagulation factors

                                                                        Bleeding

                                                                        Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                                                        Pathophysiology of DIC ndash 2 Types of Clinical pictures

                                                                        Chronic = non - overt DICMay be unrecognized clinically

                                                                        Acute = overt DIClife threatening bleedingor multiple organ failure

                                                                        Sub-Acute and Non-Overt DIC Clinical Findings

                                                                        Compensated non-overt DIC Steady low level or intermittent activation

                                                                        bull Compensated by increased production of coagulation components and platelets

                                                                        Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                                                                        Risk of decompensation leading to overt DIC

                                                                        Pathophysiology of Overt DIC

                                                                        Massive activation of coagulation and fibrinolysis

                                                                        Does not allow for compensatory efforts

                                                                        Rapid depletion of coagulation factors inhibitors and platelets

                                                                        Thrombosis multiple organ failures

                                                                        Bleeding complications and shock

                                                                        Physiopathology of DIC ndash Overt DIC Findings

                                                                        Thrombin generation

                                                                        Thrombosis

                                                                        Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                                                                        Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                                                                        Plasmin generationHemorrhage

                                                                        bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                                                                        bull Tachycardia hypotension edema

                                                                        Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                        Pathogenesis Pathways in DIC

                                                                        Cytokines

                                                                        TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                                                                        fibrin inadequateformation fibrin removal

                                                                        Fibrin deposition

                                                                        Inflammation

                                                                        Coagulation

                                                                        Stago Celebrates Lab Week 2017

                                                                        NA

                                                                        Stago 247 Educational Webinar Sites

                                                                        wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                                                                        wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                                                                        Stago Educational Apps

                                                                        HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                                                                        iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                                                                        BREAK

                                                                        Diagnostic and Management Approach for DIC

                                                                        Diagnosis of DIC

                                                                        Clinical diagnosis is obvious in cases of overt DIC

                                                                        Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                                                        Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                                                        Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                                                        Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                                                        Important to recognize simultaneous formation of thrombin and plasmin

                                                                        Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                        Lab Diagnosis of DIC ndash Screening Tests

                                                                        Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                        Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                                                        fibrinogen level) repeat testing assesses progression

                                                                        Screening tests not clinically specific or sensitive for DIC

                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                        Laboratory Changes in Overt DIC

                                                                        DIC Diagnostic Practices Over Time

                                                                        Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                        British Journal of Haematology Overt DIC Score

                                                                        Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                        ISTH Step by Step DIC Algorithm

                                                                        Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                                        US Based Validation of ISTH DIC Score

                                                                        When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                        Differential Diagnosis in DIC

                                                                        aHUS atypical hemolytic uremic syndrome

                                                                        HUS hemolytic uremic syndrome

                                                                        HIT heparin-induced thrombocytopenia

                                                                        ITP immune thrombocytopenic purpura

                                                                        TTP thrombotic thrombocytopenic purpura

                                                                        DIC and MAHA

                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                        lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                                        When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                                        DIC Management Goals

                                                                        Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                        Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                                        DIC Management and Treatment

                                                                        Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                        Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                                        requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                                        Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                                        DIC Management Strategies

                                                                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                        Anticoagulant Factor Concentrate Treatment

                                                                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                        Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                        Anticoagulant Factor Concentrate Treatment Trials

                                                                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                        Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                        Markers of Thrombin amp Plasmin Generation in DIC

                                                                        D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                        Cut-off value

                                                                        Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                        degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                        D-dimer FDPs and DIC

                                                                        D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                        Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                        Follow Up of DIC State of Disease

                                                                        Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                        Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                        FMD-Dimer in DIC Major Differences

                                                                        onset of thrombosis

                                                                        days

                                                                        Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                        FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                        D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                        of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                        0

                                                                        20

                                                                        40

                                                                        60

                                                                        80

                                                                        100

                                                                        94 85 90N = 62

                                                                        Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                        Positivity of Test Results ISTH Score and Disease State

                                                                        Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                        Red bar positive for 2 points of DIC score

                                                                        Pink bar positive for 1-2 points of DIC score

                                                                        HT hematopoietic tumor

                                                                        IF infection

                                                                        SC solid cancer

                                                                        Markers in Patients with or without DIC

                                                                        Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                        HT hematopoietic tumorIF infectionSC solid cancer

                                                                        Comparing an Automated FM vs Manual FSP Test

                                                                        Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                        Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                        Automated (Mitsubishi) vs Automated (Stago)

                                                                        In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                        Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                        In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                        In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                        In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                        Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                        No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                        Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                        Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                        Non Overt DIC Overt DIC

                                                                        AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                        Trends in Markers of DIC for Different Patients

                                                                        Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                        Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                        Trends in Markers of DIC for Different Patients

                                                                        Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                        FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                        28 day outcome survival

                                                                        28 day outcome death

                                                                        Determination of Cutoffs of FM and D-dimer in DIC

                                                                        Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                        Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                        Determination of Cutoffs of FM and D-dimer in DIC

                                                                        Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                        Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                        DIC Case Studies

                                                                        Case Study 1 - Presentation

                                                                        18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                        Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                        WBC count 77 KμL 423 ndash 907 x KμL

                                                                        RBC count 17 MμL 137 ndash 175 x MμL

                                                                        Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                        Hematocrit 195 401 ndash 510

                                                                        MCV 95 fL 790 ndash 922 fL

                                                                        MPV 12 fL 94 ndash 124 fL

                                                                        Platelet count 9 KμL 161 ndash 347 KμL

                                                                        Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                        Lymphocytes monocytes eosinophils basophils all below normal range

                                                                        PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                        APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                        Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                        D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                        Case Study 1 ndash Microscopy

                                                                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                        Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                        Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                        DIC due to TF release by APL blasts

                                                                        Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                        Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                        20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                        Case Study 2 ndash Presentation

                                                                        TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                        PT 30 sec 113 ndash 146 sec

                                                                        APTT 75 sec 25 ndash 34 sec

                                                                        D-dimer 078 microgml FEU lt050 microgml FEU

                                                                        Fibrinogen 92 mgdl 150-400 mgdl

                                                                        pH 728 738 to 742

                                                                        PaO2 570 mmHg 80-100 mmHg

                                                                        WBC 33 times 103mm3 40-11 times 103mm3

                                                                        ALT 111 IUL 0ndash34 IUL

                                                                        AST 61 IUL 0ndash34 IUL

                                                                        BUN 303 mgdL 08-13 mgdL

                                                                        Case Study 2 ndash Lab Results

                                                                        Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                        Case Study 2 ndash Diagnosis

                                                                        60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                        Case Study 3 ndash Presentation

                                                                        TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                        PT 228 sec 113 ndash 146 sec

                                                                        APTT 45 sec 25 ndash 34 sec

                                                                        D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                        Fibrinogen 82 mgdL 150-400 mgdL

                                                                        FV Normal 70-120

                                                                        FVII Normal 55-170

                                                                        FVIII Normal 60-150

                                                                        Protein C Normal 70-130

                                                                        Hb 134 gdL 14-16 gdL

                                                                        WBC 81 times 103mm3 40-11 times 103mm3

                                                                        ALT 32 IUL 0ndash34 IUL

                                                                        AST 28 IUL 0ndash34 IUL

                                                                        BUN 09 mgdL 08-13 mgdL

                                                                        Case Study 3 ndash Lab Results

                                                                        Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                        Case Study 3 ndash Diagnosis and Therapy

                                                                        Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                        Case Study 4 ndash Presentation

                                                                        TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                        PT 28 sec 113 ndash 146 sec

                                                                        APTT 71 sec 25 ndash 34 sec

                                                                        D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                        Fibrinogen 92 mgdL 150-400 mgdl

                                                                        FV Normal 70-120

                                                                        FVII Normal 55-170

                                                                        FVIII Normal 60-150

                                                                        Protein C Normal 70-130

                                                                        Hb 158 gdL 14-16 gdL

                                                                        WBC 71 times 103mm3 40-11 times 103mm3

                                                                        ALT 60 IUL 0ndash34 IUL

                                                                        AST 47 IUL 0ndash34 IUL

                                                                        BUN 38 mgdL 08-13 mgdL

                                                                        Case Study 4 ndash Lab Results

                                                                        Lyme disease with DICProvide antibiotics with supportive measures

                                                                        Case Study 4 ndash Diagnosis

                                                                        55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                        Case Study 5 ndash Presentation

                                                                        Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                        Case Study 5 ndash Lab Results and Time Course

                                                                        Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                        TEST RESULT REFERENCE RANGE

                                                                        Platelet count 33 x 109L 150-450 x 109L

                                                                        PT 215 sec 103 ndash 128 sec

                                                                        APTT 44 sec 26 ndash 36 sec

                                                                        D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                        Fibrinogen 34 mgdL 200-375 mgdl

                                                                        FII FV FVIII Low Not reported (NR)

                                                                        FVII FIX FX vWF Normal NR

                                                                        Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                        DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                        dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                        (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                        (D) Illustration demonstrating repair

                                                                        Case Study 5 ndash Diagnosis and Treatment

                                                                        Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                        29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                        Case Study 6 ndash Presentation

                                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                        Case Study 6 ndash Lab Results

                                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                        TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                        PT 63 sec gt control 113 ndash 146 sec

                                                                        INR 658 1 ndash 125

                                                                        APTT 80 sec gt control 25 ndash 34 sec

                                                                        D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                        Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                        Albumin 28 gdL NR

                                                                        Hb 58 gdL NR

                                                                        LDH 1196 UL NR

                                                                        SGPT 144 IU NR

                                                                        SGOT 88 IU NR

                                                                        Bilirubin 32 mgdL NR

                                                                        DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                        day postop

                                                                        Case Study 6 ndash Diagnosis and Treatment

                                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                        HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                        Case Study 6 ndash Discussion

                                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                        44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                        Case Study 7 ndash Presentation

                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                        On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                        Case Study 7 ndash Presentation

                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                        Case Study 7 ndash Lab Results vs Time

                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                        Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                        Case Study 7 ndash Diagnosis and Treatment

                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                        On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                        Case Study 7 ndash Diagnosis and Treatment

                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                        DIC Take Home Messages

                                                                        Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                        Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                        DIC

                                                                        Thank you Questions

                                                                        • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                        • Learning Objectives
                                                                        • Slide Number 3
                                                                        • Slide Number 4
                                                                        • Slide Number 5
                                                                        • Slide Number 6
                                                                        • Slide Number 7
                                                                        • Slide Number 8
                                                                        • Wound Sealing
                                                                        • The Three Steps of Hemostasis
                                                                        • Vessel Wall
                                                                        • Slide Number 12
                                                                        • Slide Number 13
                                                                        • Platelet Structure UnactivatedActivated
                                                                        • Primary Hemostasis
                                                                        • Primary Hemostasis Assays
                                                                        • Slide Number 17
                                                                        • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                        • Slide Number 19
                                                                        • Coagulation factors
                                                                        • Coagulation Assay Mechanisms
                                                                        • Slide Number 22
                                                                        • Fibrin Formation
                                                                        • Slide Number 24
                                                                        • Fibrinolysis Overview
                                                                        • Fibrinolysis Overview
                                                                        • Slide Number 27
                                                                        • Fibrinolysis Releases D-dimers
                                                                        • Basic Pathophysiology of DIC
                                                                        • Disseminated Intravascular Coagulation (DIC)
                                                                        • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                        • Clinical Conditions Associated With DIC
                                                                        • Frequency of DIC in Selected Disease States
                                                                        • Underlying Diseases in DIC Patients
                                                                        • Slide Number 36
                                                                        • Slide Number 37
                                                                        • Slide Number 38
                                                                        • Slide Number 39
                                                                        • Pathophysiology of DIC
                                                                        • Pathogenesis of DIC in Sepsis
                                                                        • Host Response in Severe Sepsis
                                                                        • Organ Failure in Severe Sepsis
                                                                        • Mechanism of DIC in Organ Failure
                                                                        • Interaction of Inflammation and Coagulation in Sepsis
                                                                        • Slide Number 47
                                                                        • Diverse and Opposing Effects of Thrombin
                                                                        • Coagulation and Fibrinolysis in DIC
                                                                        • Mechanism of DIC
                                                                        • Pathophysiology of DIC
                                                                        • Pathophysiology of DIC - Mechanism
                                                                        • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                        • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                        • Pathophysiology of Overt DIC
                                                                        • Physiopathology of DIC ndash Overt DIC Findings
                                                                        • Slide Number 57
                                                                        • Slide Number 58
                                                                        • Slide Number 59
                                                                        • Slide Number 60
                                                                        • Slide Number 61
                                                                        • BREAK
                                                                        • Diagnostic and Management Approach for DIC
                                                                        • Diagnosis of DIC
                                                                        • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                        • Lab Diagnosis of DIC ndash Screening Tests
                                                                        • Slide Number 67
                                                                        • Slide Number 68
                                                                        • British Journal of Haematology Overt DIC Score
                                                                        • Slide Number 70
                                                                        • Slide Number 71
                                                                        • Slide Number 72
                                                                        • Slide Number 73
                                                                        • DIC Management Goals
                                                                        • DIC Management and Treatment
                                                                        • DIC Management Strategies
                                                                        • Anticoagulant Factor Concentrate Treatment
                                                                        • Anticoagulant Factor Concentrate Treatment Trials
                                                                        • Markers of Thrombin amp Plasmin Generation in DIC
                                                                        • D-dimer FDPs and DIC
                                                                        • D-Dimer and FDPs in DIC
                                                                        • Follow Up of DIC State of Disease
                                                                        • FMD-Dimer in DIC Major Differences
                                                                        • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                        • Slide Number 85
                                                                        • Slide Number 86
                                                                        • Comparing an Automated FM vs Manual FSP Test
                                                                        • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                        • Slide Number 94
                                                                        • Slide Number 95
                                                                        • Slide Number 96
                                                                        • Slide Number 97
                                                                        • Slide Number 98
                                                                        • Slide Number 99
                                                                        • DIC Case Studies
                                                                        • Case Study 1 - Presentation
                                                                        • Case Study 1 ndash Lab Results
                                                                        • Case Study 1 ndash Microscopy
                                                                        • Case Study 1 ndash Diagnosis and Therapy
                                                                        • Slide Number 105
                                                                        • Slide Number 106
                                                                        • Slide Number 107
                                                                        • Slide Number 108
                                                                        • Slide Number 109
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                                                                        • Slide Number 121
                                                                        • Slide Number 122
                                                                        • Slide Number 123
                                                                        • Slide Number 124
                                                                        • Slide Number 125
                                                                        • DIC Take Home Messages
                                                                        • Slide Number 127
                                                                        • Slide Number 128

                                                                          Impact of DIC Status on Mortality - 1

                                                                          Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8

                                                                          Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC

                                                                          Impact of DIC Status on Mortality - 2

                                                                          Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                                                          Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients

                                                                          Impact of Age on Mortality in DIC Patients

                                                                          Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                                                          Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)

                                                                          Pathophysiology of DIC

                                                                          Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                          Pathogenesis of DIC in Sepsis

                                                                          Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15

                                                                          Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC

                                                                          Host Response in Severe Sepsis

                                                                          Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral

                                                                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                          Organ Failure in Severe Sepsis

                                                                          Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure

                                                                          Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51

                                                                          Mechanism of DIC in Organ Failure

                                                                          Underlying condition(sepsis trauma)

                                                                          Cytokines

                                                                          TF-mediatedactivation of coagulation

                                                                          Depression of inhibitory systems

                                                                          Reducesfibrinolysis

                                                                          Fibrin deposition

                                                                          Organ failure

                                                                          Inadequate fibrin removal

                                                                          Fibrinformation

                                                                          Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )

                                                                          Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705

                                                                          Interaction of Inflammation and Coagulation in Sepsis

                                                                          Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines

                                                                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                          Mechanism of Multiple Organ Failure in DIC

                                                                          Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

                                                                          Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

                                                                          lipopolysaccharides

                                                                          cytokines

                                                                          coagulation activation

                                                                          mononuclear cell

                                                                          tissue factor

                                                                          Diverse and Opposing Effects of Thrombin

                                                                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                          Coagulation and Fibrinolysis in DIC

                                                                          Soluble fibrin Polymer

                                                                          XIIIa

                                                                          D-Dimer

                                                                          E

                                                                          Fibrin clot

                                                                          Fibrin Degradation Products

                                                                          Fibrinogen Thrombin

                                                                          Fibrinogen Degradation

                                                                          Products

                                                                          D E

                                                                          Plasmin

                                                                          DFM + fibrinopeptides

                                                                          Soluble FM ComplexesPre-throm

                                                                          boticPost-throm

                                                                          botic

                                                                          Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

                                                                          Mechanism of DIC

                                                                          THROMBOSIS

                                                                          Fibrin

                                                                          Blood activationEndothelial lysisTF expression

                                                                          BLEEDING

                                                                          FDPs

                                                                          D-Dimer

                                                                          Plasmin

                                                                          Pathophysiology of DIC

                                                                          1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

                                                                          thromboplastin influx of activated cells (monocytes macrophages)

                                                                          Results in an intravascular deposition of fibrin

                                                                          Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

                                                                          Second step Consumption and depletion of coagulation factors inhibitors (Protein C

                                                                          Protein S AT) and platelets Local fibrinolytic response

                                                                          bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

                                                                          FDP and D-Dimer

                                                                          Bleeding

                                                                          Pathophysiology of DIC - Mechanism

                                                                          Systemic activation of coagulation

                                                                          Intravasculardepositionof fibrin

                                                                          Thrombosis of small and midsize vessels

                                                                          and organ failure

                                                                          Depletion of platelets and

                                                                          coagulation factors

                                                                          Bleeding

                                                                          Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                                                          Pathophysiology of DIC ndash 2 Types of Clinical pictures

                                                                          Chronic = non - overt DICMay be unrecognized clinically

                                                                          Acute = overt DIClife threatening bleedingor multiple organ failure

                                                                          Sub-Acute and Non-Overt DIC Clinical Findings

                                                                          Compensated non-overt DIC Steady low level or intermittent activation

                                                                          bull Compensated by increased production of coagulation components and platelets

                                                                          Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                                                                          Risk of decompensation leading to overt DIC

                                                                          Pathophysiology of Overt DIC

                                                                          Massive activation of coagulation and fibrinolysis

                                                                          Does not allow for compensatory efforts

                                                                          Rapid depletion of coagulation factors inhibitors and platelets

                                                                          Thrombosis multiple organ failures

                                                                          Bleeding complications and shock

                                                                          Physiopathology of DIC ndash Overt DIC Findings

                                                                          Thrombin generation

                                                                          Thrombosis

                                                                          Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                                                                          Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                                                                          Plasmin generationHemorrhage

                                                                          bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                                                                          bull Tachycardia hypotension edema

                                                                          Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                          Pathogenesis Pathways in DIC

                                                                          Cytokines

                                                                          TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                                                                          fibrin inadequateformation fibrin removal

                                                                          Fibrin deposition

                                                                          Inflammation

                                                                          Coagulation

                                                                          Stago Celebrates Lab Week 2017

                                                                          NA

                                                                          Stago 247 Educational Webinar Sites

                                                                          wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                                                                          wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                                                                          Stago Educational Apps

                                                                          HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                                                                          iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                                                                          BREAK

                                                                          Diagnostic and Management Approach for DIC

                                                                          Diagnosis of DIC

                                                                          Clinical diagnosis is obvious in cases of overt DIC

                                                                          Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                                                          Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                                                          Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                                                          Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                                                          Important to recognize simultaneous formation of thrombin and plasmin

                                                                          Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                          Lab Diagnosis of DIC ndash Screening Tests

                                                                          Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                          Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                                                          fibrinogen level) repeat testing assesses progression

                                                                          Screening tests not clinically specific or sensitive for DIC

                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                          Laboratory Changes in Overt DIC

                                                                          DIC Diagnostic Practices Over Time

                                                                          Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                          British Journal of Haematology Overt DIC Score

                                                                          Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                          ISTH Step by Step DIC Algorithm

                                                                          Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                                          US Based Validation of ISTH DIC Score

                                                                          When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                          Differential Diagnosis in DIC

                                                                          aHUS atypical hemolytic uremic syndrome

                                                                          HUS hemolytic uremic syndrome

                                                                          HIT heparin-induced thrombocytopenia

                                                                          ITP immune thrombocytopenic purpura

                                                                          TTP thrombotic thrombocytopenic purpura

                                                                          DIC and MAHA

                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                          lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                                          When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                                          DIC Management Goals

                                                                          Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                          Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                                          DIC Management and Treatment

                                                                          Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                          Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                                          requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                                          Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                                          DIC Management Strategies

                                                                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                          Anticoagulant Factor Concentrate Treatment

                                                                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                          Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                          Anticoagulant Factor Concentrate Treatment Trials

                                                                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                          Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                          Markers of Thrombin amp Plasmin Generation in DIC

                                                                          D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                          Cut-off value

                                                                          Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                          degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                          D-dimer FDPs and DIC

                                                                          D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                          Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                          Follow Up of DIC State of Disease

                                                                          Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                          Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                          FMD-Dimer in DIC Major Differences

                                                                          onset of thrombosis

                                                                          days

                                                                          Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                          FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                          D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                          of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                          0

                                                                          20

                                                                          40

                                                                          60

                                                                          80

                                                                          100

                                                                          94 85 90N = 62

                                                                          Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                          Positivity of Test Results ISTH Score and Disease State

                                                                          Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                          Red bar positive for 2 points of DIC score

                                                                          Pink bar positive for 1-2 points of DIC score

                                                                          HT hematopoietic tumor

                                                                          IF infection

                                                                          SC solid cancer

                                                                          Markers in Patients with or without DIC

                                                                          Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                          HT hematopoietic tumorIF infectionSC solid cancer

                                                                          Comparing an Automated FM vs Manual FSP Test

                                                                          Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                          Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                          Automated (Mitsubishi) vs Automated (Stago)

                                                                          In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                          Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                          In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                          In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                          In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                          Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                          No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                          Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                          Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                          Non Overt DIC Overt DIC

                                                                          AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                          Trends in Markers of DIC for Different Patients

                                                                          Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                          Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                          Trends in Markers of DIC for Different Patients

                                                                          Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                          FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                          28 day outcome survival

                                                                          28 day outcome death

                                                                          Determination of Cutoffs of FM and D-dimer in DIC

                                                                          Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                          Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                          Determination of Cutoffs of FM and D-dimer in DIC

                                                                          Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                          Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                          DIC Case Studies

                                                                          Case Study 1 - Presentation

                                                                          18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                          Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                          WBC count 77 KμL 423 ndash 907 x KμL

                                                                          RBC count 17 MμL 137 ndash 175 x MμL

                                                                          Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                          Hematocrit 195 401 ndash 510

                                                                          MCV 95 fL 790 ndash 922 fL

                                                                          MPV 12 fL 94 ndash 124 fL

                                                                          Platelet count 9 KμL 161 ndash 347 KμL

                                                                          Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                          Lymphocytes monocytes eosinophils basophils all below normal range

                                                                          PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                          APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                          Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                          D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                          Case Study 1 ndash Microscopy

                                                                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                          Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                          Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                          DIC due to TF release by APL blasts

                                                                          Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                          Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                          20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                          Case Study 2 ndash Presentation

                                                                          TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                          PT 30 sec 113 ndash 146 sec

                                                                          APTT 75 sec 25 ndash 34 sec

                                                                          D-dimer 078 microgml FEU lt050 microgml FEU

                                                                          Fibrinogen 92 mgdl 150-400 mgdl

                                                                          pH 728 738 to 742

                                                                          PaO2 570 mmHg 80-100 mmHg

                                                                          WBC 33 times 103mm3 40-11 times 103mm3

                                                                          ALT 111 IUL 0ndash34 IUL

                                                                          AST 61 IUL 0ndash34 IUL

                                                                          BUN 303 mgdL 08-13 mgdL

                                                                          Case Study 2 ndash Lab Results

                                                                          Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                          Case Study 2 ndash Diagnosis

                                                                          60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                          Case Study 3 ndash Presentation

                                                                          TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                          PT 228 sec 113 ndash 146 sec

                                                                          APTT 45 sec 25 ndash 34 sec

                                                                          D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                          Fibrinogen 82 mgdL 150-400 mgdL

                                                                          FV Normal 70-120

                                                                          FVII Normal 55-170

                                                                          FVIII Normal 60-150

                                                                          Protein C Normal 70-130

                                                                          Hb 134 gdL 14-16 gdL

                                                                          WBC 81 times 103mm3 40-11 times 103mm3

                                                                          ALT 32 IUL 0ndash34 IUL

                                                                          AST 28 IUL 0ndash34 IUL

                                                                          BUN 09 mgdL 08-13 mgdL

                                                                          Case Study 3 ndash Lab Results

                                                                          Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                          Case Study 3 ndash Diagnosis and Therapy

                                                                          Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                          Case Study 4 ndash Presentation

                                                                          TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                          PT 28 sec 113 ndash 146 sec

                                                                          APTT 71 sec 25 ndash 34 sec

                                                                          D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                          Fibrinogen 92 mgdL 150-400 mgdl

                                                                          FV Normal 70-120

                                                                          FVII Normal 55-170

                                                                          FVIII Normal 60-150

                                                                          Protein C Normal 70-130

                                                                          Hb 158 gdL 14-16 gdL

                                                                          WBC 71 times 103mm3 40-11 times 103mm3

                                                                          ALT 60 IUL 0ndash34 IUL

                                                                          AST 47 IUL 0ndash34 IUL

                                                                          BUN 38 mgdL 08-13 mgdL

                                                                          Case Study 4 ndash Lab Results

                                                                          Lyme disease with DICProvide antibiotics with supportive measures

                                                                          Case Study 4 ndash Diagnosis

                                                                          55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                          Case Study 5 ndash Presentation

                                                                          Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                          Case Study 5 ndash Lab Results and Time Course

                                                                          Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                          TEST RESULT REFERENCE RANGE

                                                                          Platelet count 33 x 109L 150-450 x 109L

                                                                          PT 215 sec 103 ndash 128 sec

                                                                          APTT 44 sec 26 ndash 36 sec

                                                                          D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                          Fibrinogen 34 mgdL 200-375 mgdl

                                                                          FII FV FVIII Low Not reported (NR)

                                                                          FVII FIX FX vWF Normal NR

                                                                          Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                          DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                          dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                          (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                          (D) Illustration demonstrating repair

                                                                          Case Study 5 ndash Diagnosis and Treatment

                                                                          Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                          29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                          Case Study 6 ndash Presentation

                                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                          Case Study 6 ndash Lab Results

                                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                          TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                          PT 63 sec gt control 113 ndash 146 sec

                                                                          INR 658 1 ndash 125

                                                                          APTT 80 sec gt control 25 ndash 34 sec

                                                                          D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                          Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                          Albumin 28 gdL NR

                                                                          Hb 58 gdL NR

                                                                          LDH 1196 UL NR

                                                                          SGPT 144 IU NR

                                                                          SGOT 88 IU NR

                                                                          Bilirubin 32 mgdL NR

                                                                          DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                          day postop

                                                                          Case Study 6 ndash Diagnosis and Treatment

                                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                          HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                          Case Study 6 ndash Discussion

                                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                          44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                          Case Study 7 ndash Presentation

                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                          On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                          Case Study 7 ndash Presentation

                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                          Case Study 7 ndash Lab Results vs Time

                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                          Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                          Case Study 7 ndash Diagnosis and Treatment

                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                          On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                          Case Study 7 ndash Diagnosis and Treatment

                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                          DIC Take Home Messages

                                                                          Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                          Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                          DIC

                                                                          Thank you Questions

                                                                          • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                          • Learning Objectives
                                                                          • Slide Number 3
                                                                          • Slide Number 4
                                                                          • Slide Number 5
                                                                          • Slide Number 6
                                                                          • Slide Number 7
                                                                          • Slide Number 8
                                                                          • Wound Sealing
                                                                          • The Three Steps of Hemostasis
                                                                          • Vessel Wall
                                                                          • Slide Number 12
                                                                          • Slide Number 13
                                                                          • Platelet Structure UnactivatedActivated
                                                                          • Primary Hemostasis
                                                                          • Primary Hemostasis Assays
                                                                          • Slide Number 17
                                                                          • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                          • Slide Number 19
                                                                          • Coagulation factors
                                                                          • Coagulation Assay Mechanisms
                                                                          • Slide Number 22
                                                                          • Fibrin Formation
                                                                          • Slide Number 24
                                                                          • Fibrinolysis Overview
                                                                          • Fibrinolysis Overview
                                                                          • Slide Number 27
                                                                          • Fibrinolysis Releases D-dimers
                                                                          • Basic Pathophysiology of DIC
                                                                          • Disseminated Intravascular Coagulation (DIC)
                                                                          • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                          • Clinical Conditions Associated With DIC
                                                                          • Frequency of DIC in Selected Disease States
                                                                          • Underlying Diseases in DIC Patients
                                                                          • Slide Number 36
                                                                          • Slide Number 37
                                                                          • Slide Number 38
                                                                          • Slide Number 39
                                                                          • Pathophysiology of DIC
                                                                          • Pathogenesis of DIC in Sepsis
                                                                          • Host Response in Severe Sepsis
                                                                          • Organ Failure in Severe Sepsis
                                                                          • Mechanism of DIC in Organ Failure
                                                                          • Interaction of Inflammation and Coagulation in Sepsis
                                                                          • Slide Number 47
                                                                          • Diverse and Opposing Effects of Thrombin
                                                                          • Coagulation and Fibrinolysis in DIC
                                                                          • Mechanism of DIC
                                                                          • Pathophysiology of DIC
                                                                          • Pathophysiology of DIC - Mechanism
                                                                          • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                          • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                          • Pathophysiology of Overt DIC
                                                                          • Physiopathology of DIC ndash Overt DIC Findings
                                                                          • Slide Number 57
                                                                          • Slide Number 58
                                                                          • Slide Number 59
                                                                          • Slide Number 60
                                                                          • Slide Number 61
                                                                          • BREAK
                                                                          • Diagnostic and Management Approach for DIC
                                                                          • Diagnosis of DIC
                                                                          • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                          • Lab Diagnosis of DIC ndash Screening Tests
                                                                          • Slide Number 67
                                                                          • Slide Number 68
                                                                          • British Journal of Haematology Overt DIC Score
                                                                          • Slide Number 70
                                                                          • Slide Number 71
                                                                          • Slide Number 72
                                                                          • Slide Number 73
                                                                          • DIC Management Goals
                                                                          • DIC Management and Treatment
                                                                          • DIC Management Strategies
                                                                          • Anticoagulant Factor Concentrate Treatment
                                                                          • Anticoagulant Factor Concentrate Treatment Trials
                                                                          • Markers of Thrombin amp Plasmin Generation in DIC
                                                                          • D-dimer FDPs and DIC
                                                                          • D-Dimer and FDPs in DIC
                                                                          • Follow Up of DIC State of Disease
                                                                          • FMD-Dimer in DIC Major Differences
                                                                          • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                          • Slide Number 85
                                                                          • Slide Number 86
                                                                          • Comparing an Automated FM vs Manual FSP Test
                                                                          • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                          • Slide Number 94
                                                                          • Slide Number 95
                                                                          • Slide Number 96
                                                                          • Slide Number 97
                                                                          • Slide Number 98
                                                                          • Slide Number 99
                                                                          • DIC Case Studies
                                                                          • Case Study 1 - Presentation
                                                                          • Case Study 1 ndash Lab Results
                                                                          • Case Study 1 ndash Microscopy
                                                                          • Case Study 1 ndash Diagnosis and Therapy
                                                                          • Slide Number 105
                                                                          • Slide Number 106
                                                                          • Slide Number 107
                                                                          • Slide Number 108
                                                                          • Slide Number 109
                                                                          • Slide Number 110
                                                                          • Slide Number 111
                                                                          • Slide Number 112
                                                                          • Slide Number 113
                                                                          • Slide Number 114
                                                                          • Slide Number 115
                                                                          • Slide Number 116
                                                                          • Slide Number 117
                                                                          • Slide Number 118
                                                                          • Slide Number 119
                                                                          • Slide Number 120
                                                                          • Slide Number 121
                                                                          • Slide Number 122
                                                                          • Slide Number 123
                                                                          • Slide Number 124
                                                                          • Slide Number 125
                                                                          • DIC Take Home Messages
                                                                          • Slide Number 127
                                                                          • Slide Number 128

                                                                            Impact of DIC Status on Mortality - 2

                                                                            Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                                                            Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients

                                                                            Impact of Age on Mortality in DIC Patients

                                                                            Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                                                            Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)

                                                                            Pathophysiology of DIC

                                                                            Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                            Pathogenesis of DIC in Sepsis

                                                                            Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15

                                                                            Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC

                                                                            Host Response in Severe Sepsis

                                                                            Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral

                                                                            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                            Organ Failure in Severe Sepsis

                                                                            Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure

                                                                            Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51

                                                                            Mechanism of DIC in Organ Failure

                                                                            Underlying condition(sepsis trauma)

                                                                            Cytokines

                                                                            TF-mediatedactivation of coagulation

                                                                            Depression of inhibitory systems

                                                                            Reducesfibrinolysis

                                                                            Fibrin deposition

                                                                            Organ failure

                                                                            Inadequate fibrin removal

                                                                            Fibrinformation

                                                                            Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )

                                                                            Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705

                                                                            Interaction of Inflammation and Coagulation in Sepsis

                                                                            Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines

                                                                            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                            Mechanism of Multiple Organ Failure in DIC

                                                                            Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

                                                                            Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

                                                                            lipopolysaccharides

                                                                            cytokines

                                                                            coagulation activation

                                                                            mononuclear cell

                                                                            tissue factor

                                                                            Diverse and Opposing Effects of Thrombin

                                                                            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                            Coagulation and Fibrinolysis in DIC

                                                                            Soluble fibrin Polymer

                                                                            XIIIa

                                                                            D-Dimer

                                                                            E

                                                                            Fibrin clot

                                                                            Fibrin Degradation Products

                                                                            Fibrinogen Thrombin

                                                                            Fibrinogen Degradation

                                                                            Products

                                                                            D E

                                                                            Plasmin

                                                                            DFM + fibrinopeptides

                                                                            Soluble FM ComplexesPre-throm

                                                                            boticPost-throm

                                                                            botic

                                                                            Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

                                                                            Mechanism of DIC

                                                                            THROMBOSIS

                                                                            Fibrin

                                                                            Blood activationEndothelial lysisTF expression

                                                                            BLEEDING

                                                                            FDPs

                                                                            D-Dimer

                                                                            Plasmin

                                                                            Pathophysiology of DIC

                                                                            1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

                                                                            thromboplastin influx of activated cells (monocytes macrophages)

                                                                            Results in an intravascular deposition of fibrin

                                                                            Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

                                                                            Second step Consumption and depletion of coagulation factors inhibitors (Protein C

                                                                            Protein S AT) and platelets Local fibrinolytic response

                                                                            bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

                                                                            FDP and D-Dimer

                                                                            Bleeding

                                                                            Pathophysiology of DIC - Mechanism

                                                                            Systemic activation of coagulation

                                                                            Intravasculardepositionof fibrin

                                                                            Thrombosis of small and midsize vessels

                                                                            and organ failure

                                                                            Depletion of platelets and

                                                                            coagulation factors

                                                                            Bleeding

                                                                            Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                                                            Pathophysiology of DIC ndash 2 Types of Clinical pictures

                                                                            Chronic = non - overt DICMay be unrecognized clinically

                                                                            Acute = overt DIClife threatening bleedingor multiple organ failure

                                                                            Sub-Acute and Non-Overt DIC Clinical Findings

                                                                            Compensated non-overt DIC Steady low level or intermittent activation

                                                                            bull Compensated by increased production of coagulation components and platelets

                                                                            Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                                                                            Risk of decompensation leading to overt DIC

                                                                            Pathophysiology of Overt DIC

                                                                            Massive activation of coagulation and fibrinolysis

                                                                            Does not allow for compensatory efforts

                                                                            Rapid depletion of coagulation factors inhibitors and platelets

                                                                            Thrombosis multiple organ failures

                                                                            Bleeding complications and shock

                                                                            Physiopathology of DIC ndash Overt DIC Findings

                                                                            Thrombin generation

                                                                            Thrombosis

                                                                            Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                                                                            Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                                                                            Plasmin generationHemorrhage

                                                                            bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                                                                            bull Tachycardia hypotension edema

                                                                            Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                            Pathogenesis Pathways in DIC

                                                                            Cytokines

                                                                            TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                                                                            fibrin inadequateformation fibrin removal

                                                                            Fibrin deposition

                                                                            Inflammation

                                                                            Coagulation

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                                                                            HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                                                                            iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                                                                            BREAK

                                                                            Diagnostic and Management Approach for DIC

                                                                            Diagnosis of DIC

                                                                            Clinical diagnosis is obvious in cases of overt DIC

                                                                            Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                                                            Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                                                            Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                                                            Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                                                            Important to recognize simultaneous formation of thrombin and plasmin

                                                                            Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                            Lab Diagnosis of DIC ndash Screening Tests

                                                                            Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                            Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                                                            fibrinogen level) repeat testing assesses progression

                                                                            Screening tests not clinically specific or sensitive for DIC

                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                            Laboratory Changes in Overt DIC

                                                                            DIC Diagnostic Practices Over Time

                                                                            Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                            British Journal of Haematology Overt DIC Score

                                                                            Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                            ISTH Step by Step DIC Algorithm

                                                                            Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                                            US Based Validation of ISTH DIC Score

                                                                            When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                            Differential Diagnosis in DIC

                                                                            aHUS atypical hemolytic uremic syndrome

                                                                            HUS hemolytic uremic syndrome

                                                                            HIT heparin-induced thrombocytopenia

                                                                            ITP immune thrombocytopenic purpura

                                                                            TTP thrombotic thrombocytopenic purpura

                                                                            DIC and MAHA

                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                            lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                                            When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                                            DIC Management Goals

                                                                            Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                            Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                                            DIC Management and Treatment

                                                                            Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                            Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                                            requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                                            Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                                            DIC Management Strategies

                                                                            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                            Anticoagulant Factor Concentrate Treatment

                                                                            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                            Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                            Anticoagulant Factor Concentrate Treatment Trials

                                                                            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                            Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                            Markers of Thrombin amp Plasmin Generation in DIC

                                                                            D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                            Cut-off value

                                                                            Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                            degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                            D-dimer FDPs and DIC

                                                                            D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                            Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                            Follow Up of DIC State of Disease

                                                                            Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                            Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                            FMD-Dimer in DIC Major Differences

                                                                            onset of thrombosis

                                                                            days

                                                                            Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                            FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                            D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                            of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                            0

                                                                            20

                                                                            40

                                                                            60

                                                                            80

                                                                            100

                                                                            94 85 90N = 62

                                                                            Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                            Positivity of Test Results ISTH Score and Disease State

                                                                            Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                            Red bar positive for 2 points of DIC score

                                                                            Pink bar positive for 1-2 points of DIC score

                                                                            HT hematopoietic tumor

                                                                            IF infection

                                                                            SC solid cancer

                                                                            Markers in Patients with or without DIC

                                                                            Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                            HT hematopoietic tumorIF infectionSC solid cancer

                                                                            Comparing an Automated FM vs Manual FSP Test

                                                                            Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                            Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                            Automated (Mitsubishi) vs Automated (Stago)

                                                                            In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                            Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                            In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                            In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                            In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                            Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                            No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                            Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                            Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                            Non Overt DIC Overt DIC

                                                                            AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                            Trends in Markers of DIC for Different Patients

                                                                            Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                            Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                            Trends in Markers of DIC for Different Patients

                                                                            Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                            FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                            28 day outcome survival

                                                                            28 day outcome death

                                                                            Determination of Cutoffs of FM and D-dimer in DIC

                                                                            Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                            Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                            Determination of Cutoffs of FM and D-dimer in DIC

                                                                            Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                            Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                            DIC Case Studies

                                                                            Case Study 1 - Presentation

                                                                            18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                            Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                            WBC count 77 KμL 423 ndash 907 x KμL

                                                                            RBC count 17 MμL 137 ndash 175 x MμL

                                                                            Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                            Hematocrit 195 401 ndash 510

                                                                            MCV 95 fL 790 ndash 922 fL

                                                                            MPV 12 fL 94 ndash 124 fL

                                                                            Platelet count 9 KμL 161 ndash 347 KμL

                                                                            Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                            Lymphocytes monocytes eosinophils basophils all below normal range

                                                                            PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                            APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                            Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                            D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                            Case Study 1 ndash Microscopy

                                                                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                            Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                            Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                            DIC due to TF release by APL blasts

                                                                            Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                            Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                            20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                            Case Study 2 ndash Presentation

                                                                            TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                            PT 30 sec 113 ndash 146 sec

                                                                            APTT 75 sec 25 ndash 34 sec

                                                                            D-dimer 078 microgml FEU lt050 microgml FEU

                                                                            Fibrinogen 92 mgdl 150-400 mgdl

                                                                            pH 728 738 to 742

                                                                            PaO2 570 mmHg 80-100 mmHg

                                                                            WBC 33 times 103mm3 40-11 times 103mm3

                                                                            ALT 111 IUL 0ndash34 IUL

                                                                            AST 61 IUL 0ndash34 IUL

                                                                            BUN 303 mgdL 08-13 mgdL

                                                                            Case Study 2 ndash Lab Results

                                                                            Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                            Case Study 2 ndash Diagnosis

                                                                            60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                            Case Study 3 ndash Presentation

                                                                            TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                            PT 228 sec 113 ndash 146 sec

                                                                            APTT 45 sec 25 ndash 34 sec

                                                                            D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                            Fibrinogen 82 mgdL 150-400 mgdL

                                                                            FV Normal 70-120

                                                                            FVII Normal 55-170

                                                                            FVIII Normal 60-150

                                                                            Protein C Normal 70-130

                                                                            Hb 134 gdL 14-16 gdL

                                                                            WBC 81 times 103mm3 40-11 times 103mm3

                                                                            ALT 32 IUL 0ndash34 IUL

                                                                            AST 28 IUL 0ndash34 IUL

                                                                            BUN 09 mgdL 08-13 mgdL

                                                                            Case Study 3 ndash Lab Results

                                                                            Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                            Case Study 3 ndash Diagnosis and Therapy

                                                                            Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                            Case Study 4 ndash Presentation

                                                                            TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                            PT 28 sec 113 ndash 146 sec

                                                                            APTT 71 sec 25 ndash 34 sec

                                                                            D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                            Fibrinogen 92 mgdL 150-400 mgdl

                                                                            FV Normal 70-120

                                                                            FVII Normal 55-170

                                                                            FVIII Normal 60-150

                                                                            Protein C Normal 70-130

                                                                            Hb 158 gdL 14-16 gdL

                                                                            WBC 71 times 103mm3 40-11 times 103mm3

                                                                            ALT 60 IUL 0ndash34 IUL

                                                                            AST 47 IUL 0ndash34 IUL

                                                                            BUN 38 mgdL 08-13 mgdL

                                                                            Case Study 4 ndash Lab Results

                                                                            Lyme disease with DICProvide antibiotics with supportive measures

                                                                            Case Study 4 ndash Diagnosis

                                                                            55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                            Case Study 5 ndash Presentation

                                                                            Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                            Case Study 5 ndash Lab Results and Time Course

                                                                            Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                            TEST RESULT REFERENCE RANGE

                                                                            Platelet count 33 x 109L 150-450 x 109L

                                                                            PT 215 sec 103 ndash 128 sec

                                                                            APTT 44 sec 26 ndash 36 sec

                                                                            D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                            Fibrinogen 34 mgdL 200-375 mgdl

                                                                            FII FV FVIII Low Not reported (NR)

                                                                            FVII FIX FX vWF Normal NR

                                                                            Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                            DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                            dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                            (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                            (D) Illustration demonstrating repair

                                                                            Case Study 5 ndash Diagnosis and Treatment

                                                                            Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                            29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                            Case Study 6 ndash Presentation

                                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                            Case Study 6 ndash Lab Results

                                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                            TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                            PT 63 sec gt control 113 ndash 146 sec

                                                                            INR 658 1 ndash 125

                                                                            APTT 80 sec gt control 25 ndash 34 sec

                                                                            D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                            Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                            Albumin 28 gdL NR

                                                                            Hb 58 gdL NR

                                                                            LDH 1196 UL NR

                                                                            SGPT 144 IU NR

                                                                            SGOT 88 IU NR

                                                                            Bilirubin 32 mgdL NR

                                                                            DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                            day postop

                                                                            Case Study 6 ndash Diagnosis and Treatment

                                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                            HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                            Case Study 6 ndash Discussion

                                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                            44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                            Case Study 7 ndash Presentation

                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                            On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                            Case Study 7 ndash Presentation

                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                            Case Study 7 ndash Lab Results vs Time

                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                            Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                            Case Study 7 ndash Diagnosis and Treatment

                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                            On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                            Case Study 7 ndash Diagnosis and Treatment

                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                            DIC Take Home Messages

                                                                            Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                            Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                            DIC

                                                                            Thank you Questions

                                                                            • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                            • Learning Objectives
                                                                            • Slide Number 3
                                                                            • Slide Number 4
                                                                            • Slide Number 5
                                                                            • Slide Number 6
                                                                            • Slide Number 7
                                                                            • Slide Number 8
                                                                            • Wound Sealing
                                                                            • The Three Steps of Hemostasis
                                                                            • Vessel Wall
                                                                            • Slide Number 12
                                                                            • Slide Number 13
                                                                            • Platelet Structure UnactivatedActivated
                                                                            • Primary Hemostasis
                                                                            • Primary Hemostasis Assays
                                                                            • Slide Number 17
                                                                            • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                            • Slide Number 19
                                                                            • Coagulation factors
                                                                            • Coagulation Assay Mechanisms
                                                                            • Slide Number 22
                                                                            • Fibrin Formation
                                                                            • Slide Number 24
                                                                            • Fibrinolysis Overview
                                                                            • Fibrinolysis Overview
                                                                            • Slide Number 27
                                                                            • Fibrinolysis Releases D-dimers
                                                                            • Basic Pathophysiology of DIC
                                                                            • Disseminated Intravascular Coagulation (DIC)
                                                                            • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                            • Clinical Conditions Associated With DIC
                                                                            • Frequency of DIC in Selected Disease States
                                                                            • Underlying Diseases in DIC Patients
                                                                            • Slide Number 36
                                                                            • Slide Number 37
                                                                            • Slide Number 38
                                                                            • Slide Number 39
                                                                            • Pathophysiology of DIC
                                                                            • Pathogenesis of DIC in Sepsis
                                                                            • Host Response in Severe Sepsis
                                                                            • Organ Failure in Severe Sepsis
                                                                            • Mechanism of DIC in Organ Failure
                                                                            • Interaction of Inflammation and Coagulation in Sepsis
                                                                            • Slide Number 47
                                                                            • Diverse and Opposing Effects of Thrombin
                                                                            • Coagulation and Fibrinolysis in DIC
                                                                            • Mechanism of DIC
                                                                            • Pathophysiology of DIC
                                                                            • Pathophysiology of DIC - Mechanism
                                                                            • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                            • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                            • Pathophysiology of Overt DIC
                                                                            • Physiopathology of DIC ndash Overt DIC Findings
                                                                            • Slide Number 57
                                                                            • Slide Number 58
                                                                            • Slide Number 59
                                                                            • Slide Number 60
                                                                            • Slide Number 61
                                                                            • BREAK
                                                                            • Diagnostic and Management Approach for DIC
                                                                            • Diagnosis of DIC
                                                                            • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                            • Lab Diagnosis of DIC ndash Screening Tests
                                                                            • Slide Number 67
                                                                            • Slide Number 68
                                                                            • British Journal of Haematology Overt DIC Score
                                                                            • Slide Number 70
                                                                            • Slide Number 71
                                                                            • Slide Number 72
                                                                            • Slide Number 73
                                                                            • DIC Management Goals
                                                                            • DIC Management and Treatment
                                                                            • DIC Management Strategies
                                                                            • Anticoagulant Factor Concentrate Treatment
                                                                            • Anticoagulant Factor Concentrate Treatment Trials
                                                                            • Markers of Thrombin amp Plasmin Generation in DIC
                                                                            • D-dimer FDPs and DIC
                                                                            • D-Dimer and FDPs in DIC
                                                                            • Follow Up of DIC State of Disease
                                                                            • FMD-Dimer in DIC Major Differences
                                                                            • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                            • Slide Number 85
                                                                            • Slide Number 86
                                                                            • Comparing an Automated FM vs Manual FSP Test
                                                                            • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                            • Slide Number 94
                                                                            • Slide Number 95
                                                                            • Slide Number 96
                                                                            • Slide Number 97
                                                                            • Slide Number 98
                                                                            • Slide Number 99
                                                                            • DIC Case Studies
                                                                            • Case Study 1 - Presentation
                                                                            • Case Study 1 ndash Lab Results
                                                                            • Case Study 1 ndash Microscopy
                                                                            • Case Study 1 ndash Diagnosis and Therapy
                                                                            • Slide Number 105
                                                                            • Slide Number 106
                                                                            • Slide Number 107
                                                                            • Slide Number 108
                                                                            • Slide Number 109
                                                                            • Slide Number 110
                                                                            • Slide Number 111
                                                                            • Slide Number 112
                                                                            • Slide Number 113
                                                                            • Slide Number 114
                                                                            • Slide Number 115
                                                                            • Slide Number 116
                                                                            • Slide Number 117
                                                                            • Slide Number 118
                                                                            • Slide Number 119
                                                                            • Slide Number 120
                                                                            • Slide Number 121
                                                                            • Slide Number 122
                                                                            • Slide Number 123
                                                                            • Slide Number 124
                                                                            • Slide Number 125
                                                                            • DIC Take Home Messages
                                                                            • Slide Number 127
                                                                            • Slide Number 128

                                                                              Impact of Age on Mortality in DIC Patients

                                                                              Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4

                                                                              Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)

                                                                              Pathophysiology of DIC

                                                                              Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                              Pathogenesis of DIC in Sepsis

                                                                              Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15

                                                                              Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC

                                                                              Host Response in Severe Sepsis

                                                                              Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral

                                                                              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                              Organ Failure in Severe Sepsis

                                                                              Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure

                                                                              Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51

                                                                              Mechanism of DIC in Organ Failure

                                                                              Underlying condition(sepsis trauma)

                                                                              Cytokines

                                                                              TF-mediatedactivation of coagulation

                                                                              Depression of inhibitory systems

                                                                              Reducesfibrinolysis

                                                                              Fibrin deposition

                                                                              Organ failure

                                                                              Inadequate fibrin removal

                                                                              Fibrinformation

                                                                              Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )

                                                                              Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705

                                                                              Interaction of Inflammation and Coagulation in Sepsis

                                                                              Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines

                                                                              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                              Mechanism of Multiple Organ Failure in DIC

                                                                              Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

                                                                              Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

                                                                              lipopolysaccharides

                                                                              cytokines

                                                                              coagulation activation

                                                                              mononuclear cell

                                                                              tissue factor

                                                                              Diverse and Opposing Effects of Thrombin

                                                                              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                              Coagulation and Fibrinolysis in DIC

                                                                              Soluble fibrin Polymer

                                                                              XIIIa

                                                                              D-Dimer

                                                                              E

                                                                              Fibrin clot

                                                                              Fibrin Degradation Products

                                                                              Fibrinogen Thrombin

                                                                              Fibrinogen Degradation

                                                                              Products

                                                                              D E

                                                                              Plasmin

                                                                              DFM + fibrinopeptides

                                                                              Soluble FM ComplexesPre-throm

                                                                              boticPost-throm

                                                                              botic

                                                                              Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

                                                                              Mechanism of DIC

                                                                              THROMBOSIS

                                                                              Fibrin

                                                                              Blood activationEndothelial lysisTF expression

                                                                              BLEEDING

                                                                              FDPs

                                                                              D-Dimer

                                                                              Plasmin

                                                                              Pathophysiology of DIC

                                                                              1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

                                                                              thromboplastin influx of activated cells (monocytes macrophages)

                                                                              Results in an intravascular deposition of fibrin

                                                                              Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

                                                                              Second step Consumption and depletion of coagulation factors inhibitors (Protein C

                                                                              Protein S AT) and platelets Local fibrinolytic response

                                                                              bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

                                                                              FDP and D-Dimer

                                                                              Bleeding

                                                                              Pathophysiology of DIC - Mechanism

                                                                              Systemic activation of coagulation

                                                                              Intravasculardepositionof fibrin

                                                                              Thrombosis of small and midsize vessels

                                                                              and organ failure

                                                                              Depletion of platelets and

                                                                              coagulation factors

                                                                              Bleeding

                                                                              Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                                                              Pathophysiology of DIC ndash 2 Types of Clinical pictures

                                                                              Chronic = non - overt DICMay be unrecognized clinically

                                                                              Acute = overt DIClife threatening bleedingor multiple organ failure

                                                                              Sub-Acute and Non-Overt DIC Clinical Findings

                                                                              Compensated non-overt DIC Steady low level or intermittent activation

                                                                              bull Compensated by increased production of coagulation components and platelets

                                                                              Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                                                                              Risk of decompensation leading to overt DIC

                                                                              Pathophysiology of Overt DIC

                                                                              Massive activation of coagulation and fibrinolysis

                                                                              Does not allow for compensatory efforts

                                                                              Rapid depletion of coagulation factors inhibitors and platelets

                                                                              Thrombosis multiple organ failures

                                                                              Bleeding complications and shock

                                                                              Physiopathology of DIC ndash Overt DIC Findings

                                                                              Thrombin generation

                                                                              Thrombosis

                                                                              Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                                                                              Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                                                                              Plasmin generationHemorrhage

                                                                              bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                                                                              bull Tachycardia hypotension edema

                                                                              Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                              Pathogenesis Pathways in DIC

                                                                              Cytokines

                                                                              TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                                                                              fibrin inadequateformation fibrin removal

                                                                              Fibrin deposition

                                                                              Inflammation

                                                                              Coagulation

                                                                              Stago Celebrates Lab Week 2017

                                                                              NA

                                                                              Stago 247 Educational Webinar Sites

                                                                              wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                                                                              wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                                                                              Stago Educational Apps

                                                                              HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                                                                              iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                                                                              BREAK

                                                                              Diagnostic and Management Approach for DIC

                                                                              Diagnosis of DIC

                                                                              Clinical diagnosis is obvious in cases of overt DIC

                                                                              Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                                                              Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                                                              Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                                                              Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                                                              Important to recognize simultaneous formation of thrombin and plasmin

                                                                              Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                              Lab Diagnosis of DIC ndash Screening Tests

                                                                              Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                              Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                                                              fibrinogen level) repeat testing assesses progression

                                                                              Screening tests not clinically specific or sensitive for DIC

                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                              Laboratory Changes in Overt DIC

                                                                              DIC Diagnostic Practices Over Time

                                                                              Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                              British Journal of Haematology Overt DIC Score

                                                                              Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                              ISTH Step by Step DIC Algorithm

                                                                              Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                                              US Based Validation of ISTH DIC Score

                                                                              When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                              Differential Diagnosis in DIC

                                                                              aHUS atypical hemolytic uremic syndrome

                                                                              HUS hemolytic uremic syndrome

                                                                              HIT heparin-induced thrombocytopenia

                                                                              ITP immune thrombocytopenic purpura

                                                                              TTP thrombotic thrombocytopenic purpura

                                                                              DIC and MAHA

                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                              lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                                              When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                                              DIC Management Goals

                                                                              Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                              Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                                              DIC Management and Treatment

                                                                              Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                              Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                                              requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                                              Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                                              DIC Management Strategies

                                                                              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                              Anticoagulant Factor Concentrate Treatment

                                                                              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                              Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                              Anticoagulant Factor Concentrate Treatment Trials

                                                                              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                              Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                              Markers of Thrombin amp Plasmin Generation in DIC

                                                                              D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                              Cut-off value

                                                                              Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                              degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                              D-dimer FDPs and DIC

                                                                              D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                              Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                              Follow Up of DIC State of Disease

                                                                              Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                              Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                              FMD-Dimer in DIC Major Differences

                                                                              onset of thrombosis

                                                                              days

                                                                              Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                              FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                              D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                              of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                              0

                                                                              20

                                                                              40

                                                                              60

                                                                              80

                                                                              100

                                                                              94 85 90N = 62

                                                                              Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                              Positivity of Test Results ISTH Score and Disease State

                                                                              Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                              Red bar positive for 2 points of DIC score

                                                                              Pink bar positive for 1-2 points of DIC score

                                                                              HT hematopoietic tumor

                                                                              IF infection

                                                                              SC solid cancer

                                                                              Markers in Patients with or without DIC

                                                                              Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                              HT hematopoietic tumorIF infectionSC solid cancer

                                                                              Comparing an Automated FM vs Manual FSP Test

                                                                              Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                              Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                              Automated (Mitsubishi) vs Automated (Stago)

                                                                              In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                              Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                              In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                              In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                              In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                              Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                              No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                              Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                              Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                              Non Overt DIC Overt DIC

                                                                              AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                              Trends in Markers of DIC for Different Patients

                                                                              Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                              Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                              Trends in Markers of DIC for Different Patients

                                                                              Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                              FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                              28 day outcome survival

                                                                              28 day outcome death

                                                                              Determination of Cutoffs of FM and D-dimer in DIC

                                                                              Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                              Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                              Determination of Cutoffs of FM and D-dimer in DIC

                                                                              Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                              Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                              DIC Case Studies

                                                                              Case Study 1 - Presentation

                                                                              18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                              Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                              WBC count 77 KμL 423 ndash 907 x KμL

                                                                              RBC count 17 MμL 137 ndash 175 x MμL

                                                                              Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                              Hematocrit 195 401 ndash 510

                                                                              MCV 95 fL 790 ndash 922 fL

                                                                              MPV 12 fL 94 ndash 124 fL

                                                                              Platelet count 9 KμL 161 ndash 347 KμL

                                                                              Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                              Lymphocytes monocytes eosinophils basophils all below normal range

                                                                              PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                              APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                              Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                              D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                              Case Study 1 ndash Microscopy

                                                                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                              Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                              Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                              DIC due to TF release by APL blasts

                                                                              Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                              Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                              20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                              Case Study 2 ndash Presentation

                                                                              TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                              PT 30 sec 113 ndash 146 sec

                                                                              APTT 75 sec 25 ndash 34 sec

                                                                              D-dimer 078 microgml FEU lt050 microgml FEU

                                                                              Fibrinogen 92 mgdl 150-400 mgdl

                                                                              pH 728 738 to 742

                                                                              PaO2 570 mmHg 80-100 mmHg

                                                                              WBC 33 times 103mm3 40-11 times 103mm3

                                                                              ALT 111 IUL 0ndash34 IUL

                                                                              AST 61 IUL 0ndash34 IUL

                                                                              BUN 303 mgdL 08-13 mgdL

                                                                              Case Study 2 ndash Lab Results

                                                                              Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                              Case Study 2 ndash Diagnosis

                                                                              60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                              Case Study 3 ndash Presentation

                                                                              TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                              PT 228 sec 113 ndash 146 sec

                                                                              APTT 45 sec 25 ndash 34 sec

                                                                              D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                              Fibrinogen 82 mgdL 150-400 mgdL

                                                                              FV Normal 70-120

                                                                              FVII Normal 55-170

                                                                              FVIII Normal 60-150

                                                                              Protein C Normal 70-130

                                                                              Hb 134 gdL 14-16 gdL

                                                                              WBC 81 times 103mm3 40-11 times 103mm3

                                                                              ALT 32 IUL 0ndash34 IUL

                                                                              AST 28 IUL 0ndash34 IUL

                                                                              BUN 09 mgdL 08-13 mgdL

                                                                              Case Study 3 ndash Lab Results

                                                                              Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                              Case Study 3 ndash Diagnosis and Therapy

                                                                              Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                              Case Study 4 ndash Presentation

                                                                              TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                              PT 28 sec 113 ndash 146 sec

                                                                              APTT 71 sec 25 ndash 34 sec

                                                                              D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                              Fibrinogen 92 mgdL 150-400 mgdl

                                                                              FV Normal 70-120

                                                                              FVII Normal 55-170

                                                                              FVIII Normal 60-150

                                                                              Protein C Normal 70-130

                                                                              Hb 158 gdL 14-16 gdL

                                                                              WBC 71 times 103mm3 40-11 times 103mm3

                                                                              ALT 60 IUL 0ndash34 IUL

                                                                              AST 47 IUL 0ndash34 IUL

                                                                              BUN 38 mgdL 08-13 mgdL

                                                                              Case Study 4 ndash Lab Results

                                                                              Lyme disease with DICProvide antibiotics with supportive measures

                                                                              Case Study 4 ndash Diagnosis

                                                                              55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                              Case Study 5 ndash Presentation

                                                                              Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                              Case Study 5 ndash Lab Results and Time Course

                                                                              Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                              TEST RESULT REFERENCE RANGE

                                                                              Platelet count 33 x 109L 150-450 x 109L

                                                                              PT 215 sec 103 ndash 128 sec

                                                                              APTT 44 sec 26 ndash 36 sec

                                                                              D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                              Fibrinogen 34 mgdL 200-375 mgdl

                                                                              FII FV FVIII Low Not reported (NR)

                                                                              FVII FIX FX vWF Normal NR

                                                                              Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                              DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                              dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                              (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                              (D) Illustration demonstrating repair

                                                                              Case Study 5 ndash Diagnosis and Treatment

                                                                              Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                              29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                              Case Study 6 ndash Presentation

                                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                              Case Study 6 ndash Lab Results

                                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                              TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                              PT 63 sec gt control 113 ndash 146 sec

                                                                              INR 658 1 ndash 125

                                                                              APTT 80 sec gt control 25 ndash 34 sec

                                                                              D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                              Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                              Albumin 28 gdL NR

                                                                              Hb 58 gdL NR

                                                                              LDH 1196 UL NR

                                                                              SGPT 144 IU NR

                                                                              SGOT 88 IU NR

                                                                              Bilirubin 32 mgdL NR

                                                                              DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                              day postop

                                                                              Case Study 6 ndash Diagnosis and Treatment

                                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                              HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                              Case Study 6 ndash Discussion

                                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                              44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                              Case Study 7 ndash Presentation

                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                              On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                              Case Study 7 ndash Presentation

                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                              Case Study 7 ndash Lab Results vs Time

                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                              Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                              Case Study 7 ndash Diagnosis and Treatment

                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                              On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                              Case Study 7 ndash Diagnosis and Treatment

                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                              DIC Take Home Messages

                                                                              Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                              Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                              DIC

                                                                              Thank you Questions

                                                                              • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                              • Learning Objectives
                                                                              • Slide Number 3
                                                                              • Slide Number 4
                                                                              • Slide Number 5
                                                                              • Slide Number 6
                                                                              • Slide Number 7
                                                                              • Slide Number 8
                                                                              • Wound Sealing
                                                                              • The Three Steps of Hemostasis
                                                                              • Vessel Wall
                                                                              • Slide Number 12
                                                                              • Slide Number 13
                                                                              • Platelet Structure UnactivatedActivated
                                                                              • Primary Hemostasis
                                                                              • Primary Hemostasis Assays
                                                                              • Slide Number 17
                                                                              • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                              • Slide Number 19
                                                                              • Coagulation factors
                                                                              • Coagulation Assay Mechanisms
                                                                              • Slide Number 22
                                                                              • Fibrin Formation
                                                                              • Slide Number 24
                                                                              • Fibrinolysis Overview
                                                                              • Fibrinolysis Overview
                                                                              • Slide Number 27
                                                                              • Fibrinolysis Releases D-dimers
                                                                              • Basic Pathophysiology of DIC
                                                                              • Disseminated Intravascular Coagulation (DIC)
                                                                              • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                              • Clinical Conditions Associated With DIC
                                                                              • Frequency of DIC in Selected Disease States
                                                                              • Underlying Diseases in DIC Patients
                                                                              • Slide Number 36
                                                                              • Slide Number 37
                                                                              • Slide Number 38
                                                                              • Slide Number 39
                                                                              • Pathophysiology of DIC
                                                                              • Pathogenesis of DIC in Sepsis
                                                                              • Host Response in Severe Sepsis
                                                                              • Organ Failure in Severe Sepsis
                                                                              • Mechanism of DIC in Organ Failure
                                                                              • Interaction of Inflammation and Coagulation in Sepsis
                                                                              • Slide Number 47
                                                                              • Diverse and Opposing Effects of Thrombin
                                                                              • Coagulation and Fibrinolysis in DIC
                                                                              • Mechanism of DIC
                                                                              • Pathophysiology of DIC
                                                                              • Pathophysiology of DIC - Mechanism
                                                                              • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                              • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                              • Pathophysiology of Overt DIC
                                                                              • Physiopathology of DIC ndash Overt DIC Findings
                                                                              • Slide Number 57
                                                                              • Slide Number 58
                                                                              • Slide Number 59
                                                                              • Slide Number 60
                                                                              • Slide Number 61
                                                                              • BREAK
                                                                              • Diagnostic and Management Approach for DIC
                                                                              • Diagnosis of DIC
                                                                              • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                              • Lab Diagnosis of DIC ndash Screening Tests
                                                                              • Slide Number 67
                                                                              • Slide Number 68
                                                                              • British Journal of Haematology Overt DIC Score
                                                                              • Slide Number 70
                                                                              • Slide Number 71
                                                                              • Slide Number 72
                                                                              • Slide Number 73
                                                                              • DIC Management Goals
                                                                              • DIC Management and Treatment
                                                                              • DIC Management Strategies
                                                                              • Anticoagulant Factor Concentrate Treatment
                                                                              • Anticoagulant Factor Concentrate Treatment Trials
                                                                              • Markers of Thrombin amp Plasmin Generation in DIC
                                                                              • D-dimer FDPs and DIC
                                                                              • D-Dimer and FDPs in DIC
                                                                              • Follow Up of DIC State of Disease
                                                                              • FMD-Dimer in DIC Major Differences
                                                                              • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                              • Slide Number 85
                                                                              • Slide Number 86
                                                                              • Comparing an Automated FM vs Manual FSP Test
                                                                              • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                              • Slide Number 94
                                                                              • Slide Number 95
                                                                              • Slide Number 96
                                                                              • Slide Number 97
                                                                              • Slide Number 98
                                                                              • Slide Number 99
                                                                              • DIC Case Studies
                                                                              • Case Study 1 - Presentation
                                                                              • Case Study 1 ndash Lab Results
                                                                              • Case Study 1 ndash Microscopy
                                                                              • Case Study 1 ndash Diagnosis and Therapy
                                                                              • Slide Number 105
                                                                              • Slide Number 106
                                                                              • Slide Number 107
                                                                              • Slide Number 108
                                                                              • Slide Number 109
                                                                              • Slide Number 110
                                                                              • Slide Number 111
                                                                              • Slide Number 112
                                                                              • Slide Number 113
                                                                              • Slide Number 114
                                                                              • Slide Number 115
                                                                              • Slide Number 116
                                                                              • Slide Number 117
                                                                              • Slide Number 118
                                                                              • Slide Number 119
                                                                              • Slide Number 120
                                                                              • Slide Number 121
                                                                              • Slide Number 122
                                                                              • Slide Number 123
                                                                              • Slide Number 124
                                                                              • Slide Number 125
                                                                              • DIC Take Home Messages
                                                                              • Slide Number 127
                                                                              • Slide Number 128

                                                                                Pathophysiology of DIC

                                                                                Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                                Pathogenesis of DIC in Sepsis

                                                                                Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15

                                                                                Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC

                                                                                Host Response in Severe Sepsis

                                                                                Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral

                                                                                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                Organ Failure in Severe Sepsis

                                                                                Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure

                                                                                Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51

                                                                                Mechanism of DIC in Organ Failure

                                                                                Underlying condition(sepsis trauma)

                                                                                Cytokines

                                                                                TF-mediatedactivation of coagulation

                                                                                Depression of inhibitory systems

                                                                                Reducesfibrinolysis

                                                                                Fibrin deposition

                                                                                Organ failure

                                                                                Inadequate fibrin removal

                                                                                Fibrinformation

                                                                                Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )

                                                                                Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705

                                                                                Interaction of Inflammation and Coagulation in Sepsis

                                                                                Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines

                                                                                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                Mechanism of Multiple Organ Failure in DIC

                                                                                Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

                                                                                Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

                                                                                lipopolysaccharides

                                                                                cytokines

                                                                                coagulation activation

                                                                                mononuclear cell

                                                                                tissue factor

                                                                                Diverse and Opposing Effects of Thrombin

                                                                                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                Coagulation and Fibrinolysis in DIC

                                                                                Soluble fibrin Polymer

                                                                                XIIIa

                                                                                D-Dimer

                                                                                E

                                                                                Fibrin clot

                                                                                Fibrin Degradation Products

                                                                                Fibrinogen Thrombin

                                                                                Fibrinogen Degradation

                                                                                Products

                                                                                D E

                                                                                Plasmin

                                                                                DFM + fibrinopeptides

                                                                                Soluble FM ComplexesPre-throm

                                                                                boticPost-throm

                                                                                botic

                                                                                Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

                                                                                Mechanism of DIC

                                                                                THROMBOSIS

                                                                                Fibrin

                                                                                Blood activationEndothelial lysisTF expression

                                                                                BLEEDING

                                                                                FDPs

                                                                                D-Dimer

                                                                                Plasmin

                                                                                Pathophysiology of DIC

                                                                                1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

                                                                                thromboplastin influx of activated cells (monocytes macrophages)

                                                                                Results in an intravascular deposition of fibrin

                                                                                Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

                                                                                Second step Consumption and depletion of coagulation factors inhibitors (Protein C

                                                                                Protein S AT) and platelets Local fibrinolytic response

                                                                                bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

                                                                                FDP and D-Dimer

                                                                                Bleeding

                                                                                Pathophysiology of DIC - Mechanism

                                                                                Systemic activation of coagulation

                                                                                Intravasculardepositionof fibrin

                                                                                Thrombosis of small and midsize vessels

                                                                                and organ failure

                                                                                Depletion of platelets and

                                                                                coagulation factors

                                                                                Bleeding

                                                                                Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                                                                Pathophysiology of DIC ndash 2 Types of Clinical pictures

                                                                                Chronic = non - overt DICMay be unrecognized clinically

                                                                                Acute = overt DIClife threatening bleedingor multiple organ failure

                                                                                Sub-Acute and Non-Overt DIC Clinical Findings

                                                                                Compensated non-overt DIC Steady low level or intermittent activation

                                                                                bull Compensated by increased production of coagulation components and platelets

                                                                                Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                                                                                Risk of decompensation leading to overt DIC

                                                                                Pathophysiology of Overt DIC

                                                                                Massive activation of coagulation and fibrinolysis

                                                                                Does not allow for compensatory efforts

                                                                                Rapid depletion of coagulation factors inhibitors and platelets

                                                                                Thrombosis multiple organ failures

                                                                                Bleeding complications and shock

                                                                                Physiopathology of DIC ndash Overt DIC Findings

                                                                                Thrombin generation

                                                                                Thrombosis

                                                                                Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                                                                                Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                                                                                Plasmin generationHemorrhage

                                                                                bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                                                                                bull Tachycardia hypotension edema

                                                                                Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                Pathogenesis Pathways in DIC

                                                                                Cytokines

                                                                                TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                                                                                fibrin inadequateformation fibrin removal

                                                                                Fibrin deposition

                                                                                Inflammation

                                                                                Coagulation

                                                                                Stago Celebrates Lab Week 2017

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                                                                                Stago 247 Educational Webinar Sites

                                                                                wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                                                                                wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                                                                                Stago Educational Apps

                                                                                HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                                                                                iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                                                                                BREAK

                                                                                Diagnostic and Management Approach for DIC

                                                                                Diagnosis of DIC

                                                                                Clinical diagnosis is obvious in cases of overt DIC

                                                                                Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                                                                Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                                                                Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                                                                Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                                                                Important to recognize simultaneous formation of thrombin and plasmin

                                                                                Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                Lab Diagnosis of DIC ndash Screening Tests

                                                                                Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                                                                fibrinogen level) repeat testing assesses progression

                                                                                Screening tests not clinically specific or sensitive for DIC

                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                Laboratory Changes in Overt DIC

                                                                                DIC Diagnostic Practices Over Time

                                                                                Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                British Journal of Haematology Overt DIC Score

                                                                                Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                ISTH Step by Step DIC Algorithm

                                                                                Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                                                US Based Validation of ISTH DIC Score

                                                                                When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                Differential Diagnosis in DIC

                                                                                aHUS atypical hemolytic uremic syndrome

                                                                                HUS hemolytic uremic syndrome

                                                                                HIT heparin-induced thrombocytopenia

                                                                                ITP immune thrombocytopenic purpura

                                                                                TTP thrombotic thrombocytopenic purpura

                                                                                DIC and MAHA

                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                                                When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                                                DIC Management Goals

                                                                                Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                                                DIC Management and Treatment

                                                                                Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                                                requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                                                Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                                                DIC Management Strategies

                                                                                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                Anticoagulant Factor Concentrate Treatment

                                                                                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                                Anticoagulant Factor Concentrate Treatment Trials

                                                                                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                                Markers of Thrombin amp Plasmin Generation in DIC

                                                                                D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                                Cut-off value

                                                                                Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                                degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                                D-dimer FDPs and DIC

                                                                                D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                                Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                                Follow Up of DIC State of Disease

                                                                                Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                                Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                                FMD-Dimer in DIC Major Differences

                                                                                onset of thrombosis

                                                                                days

                                                                                Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                                FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                                D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                                of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                                0

                                                                                20

                                                                                40

                                                                                60

                                                                                80

                                                                                100

                                                                                94 85 90N = 62

                                                                                Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                                Positivity of Test Results ISTH Score and Disease State

                                                                                Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                Red bar positive for 2 points of DIC score

                                                                                Pink bar positive for 1-2 points of DIC score

                                                                                HT hematopoietic tumor

                                                                                IF infection

                                                                                SC solid cancer

                                                                                Markers in Patients with or without DIC

                                                                                Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                HT hematopoietic tumorIF infectionSC solid cancer

                                                                                Comparing an Automated FM vs Manual FSP Test

                                                                                Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                Automated (Mitsubishi) vs Automated (Stago)

                                                                                In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                Non Overt DIC Overt DIC

                                                                                AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                Trends in Markers of DIC for Different Patients

                                                                                Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                Trends in Markers of DIC for Different Patients

                                                                                Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                28 day outcome survival

                                                                                28 day outcome death

                                                                                Determination of Cutoffs of FM and D-dimer in DIC

                                                                                Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                Determination of Cutoffs of FM and D-dimer in DIC

                                                                                Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                DIC Case Studies

                                                                                Case Study 1 - Presentation

                                                                                18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                WBC count 77 KμL 423 ndash 907 x KμL

                                                                                RBC count 17 MμL 137 ndash 175 x MμL

                                                                                Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                Hematocrit 195 401 ndash 510

                                                                                MCV 95 fL 790 ndash 922 fL

                                                                                MPV 12 fL 94 ndash 124 fL

                                                                                Platelet count 9 KμL 161 ndash 347 KμL

                                                                                Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                Case Study 1 ndash Microscopy

                                                                                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                DIC due to TF release by APL blasts

                                                                                Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                Case Study 2 ndash Presentation

                                                                                TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                PT 30 sec 113 ndash 146 sec

                                                                                APTT 75 sec 25 ndash 34 sec

                                                                                D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                Fibrinogen 92 mgdl 150-400 mgdl

                                                                                pH 728 738 to 742

                                                                                PaO2 570 mmHg 80-100 mmHg

                                                                                WBC 33 times 103mm3 40-11 times 103mm3

                                                                                ALT 111 IUL 0ndash34 IUL

                                                                                AST 61 IUL 0ndash34 IUL

                                                                                BUN 303 mgdL 08-13 mgdL

                                                                                Case Study 2 ndash Lab Results

                                                                                Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                Case Study 2 ndash Diagnosis

                                                                                60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                Case Study 3 ndash Presentation

                                                                                TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                PT 228 sec 113 ndash 146 sec

                                                                                APTT 45 sec 25 ndash 34 sec

                                                                                D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                Fibrinogen 82 mgdL 150-400 mgdL

                                                                                FV Normal 70-120

                                                                                FVII Normal 55-170

                                                                                FVIII Normal 60-150

                                                                                Protein C Normal 70-130

                                                                                Hb 134 gdL 14-16 gdL

                                                                                WBC 81 times 103mm3 40-11 times 103mm3

                                                                                ALT 32 IUL 0ndash34 IUL

                                                                                AST 28 IUL 0ndash34 IUL

                                                                                BUN 09 mgdL 08-13 mgdL

                                                                                Case Study 3 ndash Lab Results

                                                                                Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                Case Study 3 ndash Diagnosis and Therapy

                                                                                Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                Case Study 4 ndash Presentation

                                                                                TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                PT 28 sec 113 ndash 146 sec

                                                                                APTT 71 sec 25 ndash 34 sec

                                                                                D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                Fibrinogen 92 mgdL 150-400 mgdl

                                                                                FV Normal 70-120

                                                                                FVII Normal 55-170

                                                                                FVIII Normal 60-150

                                                                                Protein C Normal 70-130

                                                                                Hb 158 gdL 14-16 gdL

                                                                                WBC 71 times 103mm3 40-11 times 103mm3

                                                                                ALT 60 IUL 0ndash34 IUL

                                                                                AST 47 IUL 0ndash34 IUL

                                                                                BUN 38 mgdL 08-13 mgdL

                                                                                Case Study 4 ndash Lab Results

                                                                                Lyme disease with DICProvide antibiotics with supportive measures

                                                                                Case Study 4 ndash Diagnosis

                                                                                55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                Case Study 5 ndash Presentation

                                                                                Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                Case Study 5 ndash Lab Results and Time Course

                                                                                Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                TEST RESULT REFERENCE RANGE

                                                                                Platelet count 33 x 109L 150-450 x 109L

                                                                                PT 215 sec 103 ndash 128 sec

                                                                                APTT 44 sec 26 ndash 36 sec

                                                                                D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                Fibrinogen 34 mgdL 200-375 mgdl

                                                                                FII FV FVIII Low Not reported (NR)

                                                                                FVII FIX FX vWF Normal NR

                                                                                Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                (D) Illustration demonstrating repair

                                                                                Case Study 5 ndash Diagnosis and Treatment

                                                                                Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                Case Study 6 ndash Presentation

                                                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                Case Study 6 ndash Lab Results

                                                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                PT 63 sec gt control 113 ndash 146 sec

                                                                                INR 658 1 ndash 125

                                                                                APTT 80 sec gt control 25 ndash 34 sec

                                                                                D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                Albumin 28 gdL NR

                                                                                Hb 58 gdL NR

                                                                                LDH 1196 UL NR

                                                                                SGPT 144 IU NR

                                                                                SGOT 88 IU NR

                                                                                Bilirubin 32 mgdL NR

                                                                                DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                day postop

                                                                                Case Study 6 ndash Diagnosis and Treatment

                                                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                Case Study 6 ndash Discussion

                                                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                Case Study 7 ndash Presentation

                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                Case Study 7 ndash Presentation

                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                Case Study 7 ndash Lab Results vs Time

                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                Case Study 7 ndash Diagnosis and Treatment

                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                Case Study 7 ndash Diagnosis and Treatment

                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                DIC Take Home Messages

                                                                                Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                DIC

                                                                                Thank you Questions

                                                                                • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                • Learning Objectives
                                                                                • Slide Number 3
                                                                                • Slide Number 4
                                                                                • Slide Number 5
                                                                                • Slide Number 6
                                                                                • Slide Number 7
                                                                                • Slide Number 8
                                                                                • Wound Sealing
                                                                                • The Three Steps of Hemostasis
                                                                                • Vessel Wall
                                                                                • Slide Number 12
                                                                                • Slide Number 13
                                                                                • Platelet Structure UnactivatedActivated
                                                                                • Primary Hemostasis
                                                                                • Primary Hemostasis Assays
                                                                                • Slide Number 17
                                                                                • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                • Slide Number 19
                                                                                • Coagulation factors
                                                                                • Coagulation Assay Mechanisms
                                                                                • Slide Number 22
                                                                                • Fibrin Formation
                                                                                • Slide Number 24
                                                                                • Fibrinolysis Overview
                                                                                • Fibrinolysis Overview
                                                                                • Slide Number 27
                                                                                • Fibrinolysis Releases D-dimers
                                                                                • Basic Pathophysiology of DIC
                                                                                • Disseminated Intravascular Coagulation (DIC)
                                                                                • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                • Clinical Conditions Associated With DIC
                                                                                • Frequency of DIC in Selected Disease States
                                                                                • Underlying Diseases in DIC Patients
                                                                                • Slide Number 36
                                                                                • Slide Number 37
                                                                                • Slide Number 38
                                                                                • Slide Number 39
                                                                                • Pathophysiology of DIC
                                                                                • Pathogenesis of DIC in Sepsis
                                                                                • Host Response in Severe Sepsis
                                                                                • Organ Failure in Severe Sepsis
                                                                                • Mechanism of DIC in Organ Failure
                                                                                • Interaction of Inflammation and Coagulation in Sepsis
                                                                                • Slide Number 47
                                                                                • Diverse and Opposing Effects of Thrombin
                                                                                • Coagulation and Fibrinolysis in DIC
                                                                                • Mechanism of DIC
                                                                                • Pathophysiology of DIC
                                                                                • Pathophysiology of DIC - Mechanism
                                                                                • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                • Pathophysiology of Overt DIC
                                                                                • Physiopathology of DIC ndash Overt DIC Findings
                                                                                • Slide Number 57
                                                                                • Slide Number 58
                                                                                • Slide Number 59
                                                                                • Slide Number 60
                                                                                • Slide Number 61
                                                                                • BREAK
                                                                                • Diagnostic and Management Approach for DIC
                                                                                • Diagnosis of DIC
                                                                                • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                • Lab Diagnosis of DIC ndash Screening Tests
                                                                                • Slide Number 67
                                                                                • Slide Number 68
                                                                                • British Journal of Haematology Overt DIC Score
                                                                                • Slide Number 70
                                                                                • Slide Number 71
                                                                                • Slide Number 72
                                                                                • Slide Number 73
                                                                                • DIC Management Goals
                                                                                • DIC Management and Treatment
                                                                                • DIC Management Strategies
                                                                                • Anticoagulant Factor Concentrate Treatment
                                                                                • Anticoagulant Factor Concentrate Treatment Trials
                                                                                • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                • D-dimer FDPs and DIC
                                                                                • D-Dimer and FDPs in DIC
                                                                                • Follow Up of DIC State of Disease
                                                                                • FMD-Dimer in DIC Major Differences
                                                                                • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                • Slide Number 85
                                                                                • Slide Number 86
                                                                                • Comparing an Automated FM vs Manual FSP Test
                                                                                • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                • Slide Number 94
                                                                                • Slide Number 95
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                                                                                • DIC Case Studies
                                                                                • Case Study 1 - Presentation
                                                                                • Case Study 1 ndash Lab Results
                                                                                • Case Study 1 ndash Microscopy
                                                                                • Case Study 1 ndash Diagnosis and Therapy
                                                                                • Slide Number 105
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                                                                                • DIC Take Home Messages
                                                                                • Slide Number 127
                                                                                • Slide Number 128

                                                                                  Pathogenesis of DIC in Sepsis

                                                                                  Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15

                                                                                  Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC

                                                                                  Host Response in Severe Sepsis

                                                                                  Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral

                                                                                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                  Organ Failure in Severe Sepsis

                                                                                  Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure

                                                                                  Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51

                                                                                  Mechanism of DIC in Organ Failure

                                                                                  Underlying condition(sepsis trauma)

                                                                                  Cytokines

                                                                                  TF-mediatedactivation of coagulation

                                                                                  Depression of inhibitory systems

                                                                                  Reducesfibrinolysis

                                                                                  Fibrin deposition

                                                                                  Organ failure

                                                                                  Inadequate fibrin removal

                                                                                  Fibrinformation

                                                                                  Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )

                                                                                  Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705

                                                                                  Interaction of Inflammation and Coagulation in Sepsis

                                                                                  Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines

                                                                                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                  Mechanism of Multiple Organ Failure in DIC

                                                                                  Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

                                                                                  Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

                                                                                  lipopolysaccharides

                                                                                  cytokines

                                                                                  coagulation activation

                                                                                  mononuclear cell

                                                                                  tissue factor

                                                                                  Diverse and Opposing Effects of Thrombin

                                                                                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                  Coagulation and Fibrinolysis in DIC

                                                                                  Soluble fibrin Polymer

                                                                                  XIIIa

                                                                                  D-Dimer

                                                                                  E

                                                                                  Fibrin clot

                                                                                  Fibrin Degradation Products

                                                                                  Fibrinogen Thrombin

                                                                                  Fibrinogen Degradation

                                                                                  Products

                                                                                  D E

                                                                                  Plasmin

                                                                                  DFM + fibrinopeptides

                                                                                  Soluble FM ComplexesPre-throm

                                                                                  boticPost-throm

                                                                                  botic

                                                                                  Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

                                                                                  Mechanism of DIC

                                                                                  THROMBOSIS

                                                                                  Fibrin

                                                                                  Blood activationEndothelial lysisTF expression

                                                                                  BLEEDING

                                                                                  FDPs

                                                                                  D-Dimer

                                                                                  Plasmin

                                                                                  Pathophysiology of DIC

                                                                                  1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

                                                                                  thromboplastin influx of activated cells (monocytes macrophages)

                                                                                  Results in an intravascular deposition of fibrin

                                                                                  Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

                                                                                  Second step Consumption and depletion of coagulation factors inhibitors (Protein C

                                                                                  Protein S AT) and platelets Local fibrinolytic response

                                                                                  bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

                                                                                  FDP and D-Dimer

                                                                                  Bleeding

                                                                                  Pathophysiology of DIC - Mechanism

                                                                                  Systemic activation of coagulation

                                                                                  Intravasculardepositionof fibrin

                                                                                  Thrombosis of small and midsize vessels

                                                                                  and organ failure

                                                                                  Depletion of platelets and

                                                                                  coagulation factors

                                                                                  Bleeding

                                                                                  Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                                                                  Pathophysiology of DIC ndash 2 Types of Clinical pictures

                                                                                  Chronic = non - overt DICMay be unrecognized clinically

                                                                                  Acute = overt DIClife threatening bleedingor multiple organ failure

                                                                                  Sub-Acute and Non-Overt DIC Clinical Findings

                                                                                  Compensated non-overt DIC Steady low level or intermittent activation

                                                                                  bull Compensated by increased production of coagulation components and platelets

                                                                                  Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                                                                                  Risk of decompensation leading to overt DIC

                                                                                  Pathophysiology of Overt DIC

                                                                                  Massive activation of coagulation and fibrinolysis

                                                                                  Does not allow for compensatory efforts

                                                                                  Rapid depletion of coagulation factors inhibitors and platelets

                                                                                  Thrombosis multiple organ failures

                                                                                  Bleeding complications and shock

                                                                                  Physiopathology of DIC ndash Overt DIC Findings

                                                                                  Thrombin generation

                                                                                  Thrombosis

                                                                                  Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                                                                                  Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                                                                                  Plasmin generationHemorrhage

                                                                                  bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                                                                                  bull Tachycardia hypotension edema

                                                                                  Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                  Pathogenesis Pathways in DIC

                                                                                  Cytokines

                                                                                  TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                                                                                  fibrin inadequateformation fibrin removal

                                                                                  Fibrin deposition

                                                                                  Inflammation

                                                                                  Coagulation

                                                                                  Stago Celebrates Lab Week 2017

                                                                                  NA

                                                                                  Stago 247 Educational Webinar Sites

                                                                                  wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                                                                                  wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                                                                                  Stago Educational Apps

                                                                                  HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                                                                                  iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                                                                                  BREAK

                                                                                  Diagnostic and Management Approach for DIC

                                                                                  Diagnosis of DIC

                                                                                  Clinical diagnosis is obvious in cases of overt DIC

                                                                                  Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                                                                  Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                                                                  Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                                                                  Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                                                                  Important to recognize simultaneous formation of thrombin and plasmin

                                                                                  Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                  Lab Diagnosis of DIC ndash Screening Tests

                                                                                  Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                  Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                                                                  fibrinogen level) repeat testing assesses progression

                                                                                  Screening tests not clinically specific or sensitive for DIC

                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                  Laboratory Changes in Overt DIC

                                                                                  DIC Diagnostic Practices Over Time

                                                                                  Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                  British Journal of Haematology Overt DIC Score

                                                                                  Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                  ISTH Step by Step DIC Algorithm

                                                                                  Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                                                  US Based Validation of ISTH DIC Score

                                                                                  When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                  Differential Diagnosis in DIC

                                                                                  aHUS atypical hemolytic uremic syndrome

                                                                                  HUS hemolytic uremic syndrome

                                                                                  HIT heparin-induced thrombocytopenia

                                                                                  ITP immune thrombocytopenic purpura

                                                                                  TTP thrombotic thrombocytopenic purpura

                                                                                  DIC and MAHA

                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                  lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                                                  When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                                                  DIC Management Goals

                                                                                  Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                  Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                                                  DIC Management and Treatment

                                                                                  Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                  Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                                                  requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                                                  Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                                                  DIC Management Strategies

                                                                                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                  Anticoagulant Factor Concentrate Treatment

                                                                                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                  Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                                  Anticoagulant Factor Concentrate Treatment Trials

                                                                                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                  Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                                  Markers of Thrombin amp Plasmin Generation in DIC

                                                                                  D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                                  Cut-off value

                                                                                  Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                                  degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                                  D-dimer FDPs and DIC

                                                                                  D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                                  Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                                  Follow Up of DIC State of Disease

                                                                                  Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                                  Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                                  FMD-Dimer in DIC Major Differences

                                                                                  onset of thrombosis

                                                                                  days

                                                                                  Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                                  FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                                  D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                                  of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                                  0

                                                                                  20

                                                                                  40

                                                                                  60

                                                                                  80

                                                                                  100

                                                                                  94 85 90N = 62

                                                                                  Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                                  Positivity of Test Results ISTH Score and Disease State

                                                                                  Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                  Red bar positive for 2 points of DIC score

                                                                                  Pink bar positive for 1-2 points of DIC score

                                                                                  HT hematopoietic tumor

                                                                                  IF infection

                                                                                  SC solid cancer

                                                                                  Markers in Patients with or without DIC

                                                                                  Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                  HT hematopoietic tumorIF infectionSC solid cancer

                                                                                  Comparing an Automated FM vs Manual FSP Test

                                                                                  Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                  Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                  Automated (Mitsubishi) vs Automated (Stago)

                                                                                  In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                  Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                  In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                  In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                  In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                  Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                  No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                  Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                  Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                  Non Overt DIC Overt DIC

                                                                                  AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                  Trends in Markers of DIC for Different Patients

                                                                                  Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                  Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                  Trends in Markers of DIC for Different Patients

                                                                                  Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                  FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                  28 day outcome survival

                                                                                  28 day outcome death

                                                                                  Determination of Cutoffs of FM and D-dimer in DIC

                                                                                  Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                  Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                  Determination of Cutoffs of FM and D-dimer in DIC

                                                                                  Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                  Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                  DIC Case Studies

                                                                                  Case Study 1 - Presentation

                                                                                  18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                  Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                  WBC count 77 KμL 423 ndash 907 x KμL

                                                                                  RBC count 17 MμL 137 ndash 175 x MμL

                                                                                  Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                  Hematocrit 195 401 ndash 510

                                                                                  MCV 95 fL 790 ndash 922 fL

                                                                                  MPV 12 fL 94 ndash 124 fL

                                                                                  Platelet count 9 KμL 161 ndash 347 KμL

                                                                                  Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                  Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                  PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                  APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                  Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                  D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                  Case Study 1 ndash Microscopy

                                                                                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                  Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                  Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                  DIC due to TF release by APL blasts

                                                                                  Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                  Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                  20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                  Case Study 2 ndash Presentation

                                                                                  TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                  PT 30 sec 113 ndash 146 sec

                                                                                  APTT 75 sec 25 ndash 34 sec

                                                                                  D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                  Fibrinogen 92 mgdl 150-400 mgdl

                                                                                  pH 728 738 to 742

                                                                                  PaO2 570 mmHg 80-100 mmHg

                                                                                  WBC 33 times 103mm3 40-11 times 103mm3

                                                                                  ALT 111 IUL 0ndash34 IUL

                                                                                  AST 61 IUL 0ndash34 IUL

                                                                                  BUN 303 mgdL 08-13 mgdL

                                                                                  Case Study 2 ndash Lab Results

                                                                                  Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                  Case Study 2 ndash Diagnosis

                                                                                  60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                  Case Study 3 ndash Presentation

                                                                                  TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                  PT 228 sec 113 ndash 146 sec

                                                                                  APTT 45 sec 25 ndash 34 sec

                                                                                  D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                  Fibrinogen 82 mgdL 150-400 mgdL

                                                                                  FV Normal 70-120

                                                                                  FVII Normal 55-170

                                                                                  FVIII Normal 60-150

                                                                                  Protein C Normal 70-130

                                                                                  Hb 134 gdL 14-16 gdL

                                                                                  WBC 81 times 103mm3 40-11 times 103mm3

                                                                                  ALT 32 IUL 0ndash34 IUL

                                                                                  AST 28 IUL 0ndash34 IUL

                                                                                  BUN 09 mgdL 08-13 mgdL

                                                                                  Case Study 3 ndash Lab Results

                                                                                  Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                  Case Study 3 ndash Diagnosis and Therapy

                                                                                  Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                  Case Study 4 ndash Presentation

                                                                                  TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                  PT 28 sec 113 ndash 146 sec

                                                                                  APTT 71 sec 25 ndash 34 sec

                                                                                  D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                  Fibrinogen 92 mgdL 150-400 mgdl

                                                                                  FV Normal 70-120

                                                                                  FVII Normal 55-170

                                                                                  FVIII Normal 60-150

                                                                                  Protein C Normal 70-130

                                                                                  Hb 158 gdL 14-16 gdL

                                                                                  WBC 71 times 103mm3 40-11 times 103mm3

                                                                                  ALT 60 IUL 0ndash34 IUL

                                                                                  AST 47 IUL 0ndash34 IUL

                                                                                  BUN 38 mgdL 08-13 mgdL

                                                                                  Case Study 4 ndash Lab Results

                                                                                  Lyme disease with DICProvide antibiotics with supportive measures

                                                                                  Case Study 4 ndash Diagnosis

                                                                                  55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                  Case Study 5 ndash Presentation

                                                                                  Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                  Case Study 5 ndash Lab Results and Time Course

                                                                                  Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                  TEST RESULT REFERENCE RANGE

                                                                                  Platelet count 33 x 109L 150-450 x 109L

                                                                                  PT 215 sec 103 ndash 128 sec

                                                                                  APTT 44 sec 26 ndash 36 sec

                                                                                  D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                  Fibrinogen 34 mgdL 200-375 mgdl

                                                                                  FII FV FVIII Low Not reported (NR)

                                                                                  FVII FIX FX vWF Normal NR

                                                                                  Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                  DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                  dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                  (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                  (D) Illustration demonstrating repair

                                                                                  Case Study 5 ndash Diagnosis and Treatment

                                                                                  Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                  29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                  Case Study 6 ndash Presentation

                                                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                  Case Study 6 ndash Lab Results

                                                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                  TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                  PT 63 sec gt control 113 ndash 146 sec

                                                                                  INR 658 1 ndash 125

                                                                                  APTT 80 sec gt control 25 ndash 34 sec

                                                                                  D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                  Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                  Albumin 28 gdL NR

                                                                                  Hb 58 gdL NR

                                                                                  LDH 1196 UL NR

                                                                                  SGPT 144 IU NR

                                                                                  SGOT 88 IU NR

                                                                                  Bilirubin 32 mgdL NR

                                                                                  DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                  day postop

                                                                                  Case Study 6 ndash Diagnosis and Treatment

                                                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                  HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                  Case Study 6 ndash Discussion

                                                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                  44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                  Case Study 7 ndash Presentation

                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                  On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                  Case Study 7 ndash Presentation

                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                  Case Study 7 ndash Lab Results vs Time

                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                  Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                  Case Study 7 ndash Diagnosis and Treatment

                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                  On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                  Case Study 7 ndash Diagnosis and Treatment

                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                  DIC Take Home Messages

                                                                                  Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                  Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                  DIC

                                                                                  Thank you Questions

                                                                                  • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                  • Learning Objectives
                                                                                  • Slide Number 3
                                                                                  • Slide Number 4
                                                                                  • Slide Number 5
                                                                                  • Slide Number 6
                                                                                  • Slide Number 7
                                                                                  • Slide Number 8
                                                                                  • Wound Sealing
                                                                                  • The Three Steps of Hemostasis
                                                                                  • Vessel Wall
                                                                                  • Slide Number 12
                                                                                  • Slide Number 13
                                                                                  • Platelet Structure UnactivatedActivated
                                                                                  • Primary Hemostasis
                                                                                  • Primary Hemostasis Assays
                                                                                  • Slide Number 17
                                                                                  • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                  • Slide Number 19
                                                                                  • Coagulation factors
                                                                                  • Coagulation Assay Mechanisms
                                                                                  • Slide Number 22
                                                                                  • Fibrin Formation
                                                                                  • Slide Number 24
                                                                                  • Fibrinolysis Overview
                                                                                  • Fibrinolysis Overview
                                                                                  • Slide Number 27
                                                                                  • Fibrinolysis Releases D-dimers
                                                                                  • Basic Pathophysiology of DIC
                                                                                  • Disseminated Intravascular Coagulation (DIC)
                                                                                  • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                  • Clinical Conditions Associated With DIC
                                                                                  • Frequency of DIC in Selected Disease States
                                                                                  • Underlying Diseases in DIC Patients
                                                                                  • Slide Number 36
                                                                                  • Slide Number 37
                                                                                  • Slide Number 38
                                                                                  • Slide Number 39
                                                                                  • Pathophysiology of DIC
                                                                                  • Pathogenesis of DIC in Sepsis
                                                                                  • Host Response in Severe Sepsis
                                                                                  • Organ Failure in Severe Sepsis
                                                                                  • Mechanism of DIC in Organ Failure
                                                                                  • Interaction of Inflammation and Coagulation in Sepsis
                                                                                  • Slide Number 47
                                                                                  • Diverse and Opposing Effects of Thrombin
                                                                                  • Coagulation and Fibrinolysis in DIC
                                                                                  • Mechanism of DIC
                                                                                  • Pathophysiology of DIC
                                                                                  • Pathophysiology of DIC - Mechanism
                                                                                  • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                  • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                  • Pathophysiology of Overt DIC
                                                                                  • Physiopathology of DIC ndash Overt DIC Findings
                                                                                  • Slide Number 57
                                                                                  • Slide Number 58
                                                                                  • Slide Number 59
                                                                                  • Slide Number 60
                                                                                  • Slide Number 61
                                                                                  • BREAK
                                                                                  • Diagnostic and Management Approach for DIC
                                                                                  • Diagnosis of DIC
                                                                                  • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                  • Lab Diagnosis of DIC ndash Screening Tests
                                                                                  • Slide Number 67
                                                                                  • Slide Number 68
                                                                                  • British Journal of Haematology Overt DIC Score
                                                                                  • Slide Number 70
                                                                                  • Slide Number 71
                                                                                  • Slide Number 72
                                                                                  • Slide Number 73
                                                                                  • DIC Management Goals
                                                                                  • DIC Management and Treatment
                                                                                  • DIC Management Strategies
                                                                                  • Anticoagulant Factor Concentrate Treatment
                                                                                  • Anticoagulant Factor Concentrate Treatment Trials
                                                                                  • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                  • D-dimer FDPs and DIC
                                                                                  • D-Dimer and FDPs in DIC
                                                                                  • Follow Up of DIC State of Disease
                                                                                  • FMD-Dimer in DIC Major Differences
                                                                                  • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                  • Slide Number 85
                                                                                  • Slide Number 86
                                                                                  • Comparing an Automated FM vs Manual FSP Test
                                                                                  • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                  • Slide Number 94
                                                                                  • Slide Number 95
                                                                                  • Slide Number 96
                                                                                  • Slide Number 97
                                                                                  • Slide Number 98
                                                                                  • Slide Number 99
                                                                                  • DIC Case Studies
                                                                                  • Case Study 1 - Presentation
                                                                                  • Case Study 1 ndash Lab Results
                                                                                  • Case Study 1 ndash Microscopy
                                                                                  • Case Study 1 ndash Diagnosis and Therapy
                                                                                  • Slide Number 105
                                                                                  • Slide Number 106
                                                                                  • Slide Number 107
                                                                                  • Slide Number 108
                                                                                  • Slide Number 109
                                                                                  • Slide Number 110
                                                                                  • Slide Number 111
                                                                                  • Slide Number 112
                                                                                  • Slide Number 113
                                                                                  • Slide Number 114
                                                                                  • Slide Number 115
                                                                                  • Slide Number 116
                                                                                  • Slide Number 117
                                                                                  • Slide Number 118
                                                                                  • Slide Number 119
                                                                                  • Slide Number 120
                                                                                  • Slide Number 121
                                                                                  • Slide Number 122
                                                                                  • Slide Number 123
                                                                                  • Slide Number 124
                                                                                  • Slide Number 125
                                                                                  • DIC Take Home Messages
                                                                                  • Slide Number 127
                                                                                  • Slide Number 128

                                                                                    Host Response in Severe Sepsis

                                                                                    Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral

                                                                                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                    Organ Failure in Severe Sepsis

                                                                                    Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure

                                                                                    Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51

                                                                                    Mechanism of DIC in Organ Failure

                                                                                    Underlying condition(sepsis trauma)

                                                                                    Cytokines

                                                                                    TF-mediatedactivation of coagulation

                                                                                    Depression of inhibitory systems

                                                                                    Reducesfibrinolysis

                                                                                    Fibrin deposition

                                                                                    Organ failure

                                                                                    Inadequate fibrin removal

                                                                                    Fibrinformation

                                                                                    Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )

                                                                                    Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705

                                                                                    Interaction of Inflammation and Coagulation in Sepsis

                                                                                    Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines

                                                                                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                    Mechanism of Multiple Organ Failure in DIC

                                                                                    Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

                                                                                    Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

                                                                                    lipopolysaccharides

                                                                                    cytokines

                                                                                    coagulation activation

                                                                                    mononuclear cell

                                                                                    tissue factor

                                                                                    Diverse and Opposing Effects of Thrombin

                                                                                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                    Coagulation and Fibrinolysis in DIC

                                                                                    Soluble fibrin Polymer

                                                                                    XIIIa

                                                                                    D-Dimer

                                                                                    E

                                                                                    Fibrin clot

                                                                                    Fibrin Degradation Products

                                                                                    Fibrinogen Thrombin

                                                                                    Fibrinogen Degradation

                                                                                    Products

                                                                                    D E

                                                                                    Plasmin

                                                                                    DFM + fibrinopeptides

                                                                                    Soluble FM ComplexesPre-throm

                                                                                    boticPost-throm

                                                                                    botic

                                                                                    Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

                                                                                    Mechanism of DIC

                                                                                    THROMBOSIS

                                                                                    Fibrin

                                                                                    Blood activationEndothelial lysisTF expression

                                                                                    BLEEDING

                                                                                    FDPs

                                                                                    D-Dimer

                                                                                    Plasmin

                                                                                    Pathophysiology of DIC

                                                                                    1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

                                                                                    thromboplastin influx of activated cells (monocytes macrophages)

                                                                                    Results in an intravascular deposition of fibrin

                                                                                    Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

                                                                                    Second step Consumption and depletion of coagulation factors inhibitors (Protein C

                                                                                    Protein S AT) and platelets Local fibrinolytic response

                                                                                    bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

                                                                                    FDP and D-Dimer

                                                                                    Bleeding

                                                                                    Pathophysiology of DIC - Mechanism

                                                                                    Systemic activation of coagulation

                                                                                    Intravasculardepositionof fibrin

                                                                                    Thrombosis of small and midsize vessels

                                                                                    and organ failure

                                                                                    Depletion of platelets and

                                                                                    coagulation factors

                                                                                    Bleeding

                                                                                    Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                                                                    Pathophysiology of DIC ndash 2 Types of Clinical pictures

                                                                                    Chronic = non - overt DICMay be unrecognized clinically

                                                                                    Acute = overt DIClife threatening bleedingor multiple organ failure

                                                                                    Sub-Acute and Non-Overt DIC Clinical Findings

                                                                                    Compensated non-overt DIC Steady low level or intermittent activation

                                                                                    bull Compensated by increased production of coagulation components and platelets

                                                                                    Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                                                                                    Risk of decompensation leading to overt DIC

                                                                                    Pathophysiology of Overt DIC

                                                                                    Massive activation of coagulation and fibrinolysis

                                                                                    Does not allow for compensatory efforts

                                                                                    Rapid depletion of coagulation factors inhibitors and platelets

                                                                                    Thrombosis multiple organ failures

                                                                                    Bleeding complications and shock

                                                                                    Physiopathology of DIC ndash Overt DIC Findings

                                                                                    Thrombin generation

                                                                                    Thrombosis

                                                                                    Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                                                                                    Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                                                                                    Plasmin generationHemorrhage

                                                                                    bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                                                                                    bull Tachycardia hypotension edema

                                                                                    Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                    Pathogenesis Pathways in DIC

                                                                                    Cytokines

                                                                                    TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                                                                                    fibrin inadequateformation fibrin removal

                                                                                    Fibrin deposition

                                                                                    Inflammation

                                                                                    Coagulation

                                                                                    Stago Celebrates Lab Week 2017

                                                                                    NA

                                                                                    Stago 247 Educational Webinar Sites

                                                                                    wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                                                                                    wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                                                                                    Stago Educational Apps

                                                                                    HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                                                                                    iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                                                                                    BREAK

                                                                                    Diagnostic and Management Approach for DIC

                                                                                    Diagnosis of DIC

                                                                                    Clinical diagnosis is obvious in cases of overt DIC

                                                                                    Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                                                                    Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                                                                    Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                                                                    Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                                                                    Important to recognize simultaneous formation of thrombin and plasmin

                                                                                    Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                    Lab Diagnosis of DIC ndash Screening Tests

                                                                                    Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                    Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                                                                    fibrinogen level) repeat testing assesses progression

                                                                                    Screening tests not clinically specific or sensitive for DIC

                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                    Laboratory Changes in Overt DIC

                                                                                    DIC Diagnostic Practices Over Time

                                                                                    Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                    British Journal of Haematology Overt DIC Score

                                                                                    Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                    ISTH Step by Step DIC Algorithm

                                                                                    Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                                                    US Based Validation of ISTH DIC Score

                                                                                    When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                    Differential Diagnosis in DIC

                                                                                    aHUS atypical hemolytic uremic syndrome

                                                                                    HUS hemolytic uremic syndrome

                                                                                    HIT heparin-induced thrombocytopenia

                                                                                    ITP immune thrombocytopenic purpura

                                                                                    TTP thrombotic thrombocytopenic purpura

                                                                                    DIC and MAHA

                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                    lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                                                    When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                                                    DIC Management Goals

                                                                                    Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                    Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                                                    DIC Management and Treatment

                                                                                    Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                    Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                                                    requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                                                    Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                                                    DIC Management Strategies

                                                                                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                    Anticoagulant Factor Concentrate Treatment

                                                                                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                    Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                                    Anticoagulant Factor Concentrate Treatment Trials

                                                                                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                    Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                                    Markers of Thrombin amp Plasmin Generation in DIC

                                                                                    D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                                    Cut-off value

                                                                                    Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                                    degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                                    D-dimer FDPs and DIC

                                                                                    D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                                    Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                                    Follow Up of DIC State of Disease

                                                                                    Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                                    Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                                    FMD-Dimer in DIC Major Differences

                                                                                    onset of thrombosis

                                                                                    days

                                                                                    Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                                    FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                                    D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                                    of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                                    0

                                                                                    20

                                                                                    40

                                                                                    60

                                                                                    80

                                                                                    100

                                                                                    94 85 90N = 62

                                                                                    Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                                    Positivity of Test Results ISTH Score and Disease State

                                                                                    Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                    Red bar positive for 2 points of DIC score

                                                                                    Pink bar positive for 1-2 points of DIC score

                                                                                    HT hematopoietic tumor

                                                                                    IF infection

                                                                                    SC solid cancer

                                                                                    Markers in Patients with or without DIC

                                                                                    Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                    HT hematopoietic tumorIF infectionSC solid cancer

                                                                                    Comparing an Automated FM vs Manual FSP Test

                                                                                    Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                    Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                    Automated (Mitsubishi) vs Automated (Stago)

                                                                                    In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                    Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                    In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                    In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                    In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                    Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                    No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                    Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                    Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                    Non Overt DIC Overt DIC

                                                                                    AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                    Trends in Markers of DIC for Different Patients

                                                                                    Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                    Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                    Trends in Markers of DIC for Different Patients

                                                                                    Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                    FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                    28 day outcome survival

                                                                                    28 day outcome death

                                                                                    Determination of Cutoffs of FM and D-dimer in DIC

                                                                                    Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                    Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                    Determination of Cutoffs of FM and D-dimer in DIC

                                                                                    Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                    Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                    DIC Case Studies

                                                                                    Case Study 1 - Presentation

                                                                                    18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                    Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                    WBC count 77 KμL 423 ndash 907 x KμL

                                                                                    RBC count 17 MμL 137 ndash 175 x MμL

                                                                                    Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                    Hematocrit 195 401 ndash 510

                                                                                    MCV 95 fL 790 ndash 922 fL

                                                                                    MPV 12 fL 94 ndash 124 fL

                                                                                    Platelet count 9 KμL 161 ndash 347 KμL

                                                                                    Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                    Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                    PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                    APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                    Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                    D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                    Case Study 1 ndash Microscopy

                                                                                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                    Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                    Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                    DIC due to TF release by APL blasts

                                                                                    Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                    Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                    20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                    Case Study 2 ndash Presentation

                                                                                    TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                    PT 30 sec 113 ndash 146 sec

                                                                                    APTT 75 sec 25 ndash 34 sec

                                                                                    D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                    Fibrinogen 92 mgdl 150-400 mgdl

                                                                                    pH 728 738 to 742

                                                                                    PaO2 570 mmHg 80-100 mmHg

                                                                                    WBC 33 times 103mm3 40-11 times 103mm3

                                                                                    ALT 111 IUL 0ndash34 IUL

                                                                                    AST 61 IUL 0ndash34 IUL

                                                                                    BUN 303 mgdL 08-13 mgdL

                                                                                    Case Study 2 ndash Lab Results

                                                                                    Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                    Case Study 2 ndash Diagnosis

                                                                                    60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                    Case Study 3 ndash Presentation

                                                                                    TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                    PT 228 sec 113 ndash 146 sec

                                                                                    APTT 45 sec 25 ndash 34 sec

                                                                                    D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                    Fibrinogen 82 mgdL 150-400 mgdL

                                                                                    FV Normal 70-120

                                                                                    FVII Normal 55-170

                                                                                    FVIII Normal 60-150

                                                                                    Protein C Normal 70-130

                                                                                    Hb 134 gdL 14-16 gdL

                                                                                    WBC 81 times 103mm3 40-11 times 103mm3

                                                                                    ALT 32 IUL 0ndash34 IUL

                                                                                    AST 28 IUL 0ndash34 IUL

                                                                                    BUN 09 mgdL 08-13 mgdL

                                                                                    Case Study 3 ndash Lab Results

                                                                                    Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                    Case Study 3 ndash Diagnosis and Therapy

                                                                                    Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                    Case Study 4 ndash Presentation

                                                                                    TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                    PT 28 sec 113 ndash 146 sec

                                                                                    APTT 71 sec 25 ndash 34 sec

                                                                                    D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                    Fibrinogen 92 mgdL 150-400 mgdl

                                                                                    FV Normal 70-120

                                                                                    FVII Normal 55-170

                                                                                    FVIII Normal 60-150

                                                                                    Protein C Normal 70-130

                                                                                    Hb 158 gdL 14-16 gdL

                                                                                    WBC 71 times 103mm3 40-11 times 103mm3

                                                                                    ALT 60 IUL 0ndash34 IUL

                                                                                    AST 47 IUL 0ndash34 IUL

                                                                                    BUN 38 mgdL 08-13 mgdL

                                                                                    Case Study 4 ndash Lab Results

                                                                                    Lyme disease with DICProvide antibiotics with supportive measures

                                                                                    Case Study 4 ndash Diagnosis

                                                                                    55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                    Case Study 5 ndash Presentation

                                                                                    Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                    Case Study 5 ndash Lab Results and Time Course

                                                                                    Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                    TEST RESULT REFERENCE RANGE

                                                                                    Platelet count 33 x 109L 150-450 x 109L

                                                                                    PT 215 sec 103 ndash 128 sec

                                                                                    APTT 44 sec 26 ndash 36 sec

                                                                                    D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                    Fibrinogen 34 mgdL 200-375 mgdl

                                                                                    FII FV FVIII Low Not reported (NR)

                                                                                    FVII FIX FX vWF Normal NR

                                                                                    Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                    DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                    dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                    (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                    (D) Illustration demonstrating repair

                                                                                    Case Study 5 ndash Diagnosis and Treatment

                                                                                    Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                    29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                    Case Study 6 ndash Presentation

                                                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                    Case Study 6 ndash Lab Results

                                                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                    TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                    PT 63 sec gt control 113 ndash 146 sec

                                                                                    INR 658 1 ndash 125

                                                                                    APTT 80 sec gt control 25 ndash 34 sec

                                                                                    D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                    Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                    Albumin 28 gdL NR

                                                                                    Hb 58 gdL NR

                                                                                    LDH 1196 UL NR

                                                                                    SGPT 144 IU NR

                                                                                    SGOT 88 IU NR

                                                                                    Bilirubin 32 mgdL NR

                                                                                    DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                    day postop

                                                                                    Case Study 6 ndash Diagnosis and Treatment

                                                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                    HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                    Case Study 6 ndash Discussion

                                                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                    44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                    Case Study 7 ndash Presentation

                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                    On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                    Case Study 7 ndash Presentation

                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                    Case Study 7 ndash Lab Results vs Time

                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                    Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                    Case Study 7 ndash Diagnosis and Treatment

                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                    On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                    Case Study 7 ndash Diagnosis and Treatment

                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                    DIC Take Home Messages

                                                                                    Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                    Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                    DIC

                                                                                    Thank you Questions

                                                                                    • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                    • Learning Objectives
                                                                                    • Slide Number 3
                                                                                    • Slide Number 4
                                                                                    • Slide Number 5
                                                                                    • Slide Number 6
                                                                                    • Slide Number 7
                                                                                    • Slide Number 8
                                                                                    • Wound Sealing
                                                                                    • The Three Steps of Hemostasis
                                                                                    • Vessel Wall
                                                                                    • Slide Number 12
                                                                                    • Slide Number 13
                                                                                    • Platelet Structure UnactivatedActivated
                                                                                    • Primary Hemostasis
                                                                                    • Primary Hemostasis Assays
                                                                                    • Slide Number 17
                                                                                    • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                    • Slide Number 19
                                                                                    • Coagulation factors
                                                                                    • Coagulation Assay Mechanisms
                                                                                    • Slide Number 22
                                                                                    • Fibrin Formation
                                                                                    • Slide Number 24
                                                                                    • Fibrinolysis Overview
                                                                                    • Fibrinolysis Overview
                                                                                    • Slide Number 27
                                                                                    • Fibrinolysis Releases D-dimers
                                                                                    • Basic Pathophysiology of DIC
                                                                                    • Disseminated Intravascular Coagulation (DIC)
                                                                                    • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                    • Clinical Conditions Associated With DIC
                                                                                    • Frequency of DIC in Selected Disease States
                                                                                    • Underlying Diseases in DIC Patients
                                                                                    • Slide Number 36
                                                                                    • Slide Number 37
                                                                                    • Slide Number 38
                                                                                    • Slide Number 39
                                                                                    • Pathophysiology of DIC
                                                                                    • Pathogenesis of DIC in Sepsis
                                                                                    • Host Response in Severe Sepsis
                                                                                    • Organ Failure in Severe Sepsis
                                                                                    • Mechanism of DIC in Organ Failure
                                                                                    • Interaction of Inflammation and Coagulation in Sepsis
                                                                                    • Slide Number 47
                                                                                    • Diverse and Opposing Effects of Thrombin
                                                                                    • Coagulation and Fibrinolysis in DIC
                                                                                    • Mechanism of DIC
                                                                                    • Pathophysiology of DIC
                                                                                    • Pathophysiology of DIC - Mechanism
                                                                                    • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                    • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                    • Pathophysiology of Overt DIC
                                                                                    • Physiopathology of DIC ndash Overt DIC Findings
                                                                                    • Slide Number 57
                                                                                    • Slide Number 58
                                                                                    • Slide Number 59
                                                                                    • Slide Number 60
                                                                                    • Slide Number 61
                                                                                    • BREAK
                                                                                    • Diagnostic and Management Approach for DIC
                                                                                    • Diagnosis of DIC
                                                                                    • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                    • Lab Diagnosis of DIC ndash Screening Tests
                                                                                    • Slide Number 67
                                                                                    • Slide Number 68
                                                                                    • British Journal of Haematology Overt DIC Score
                                                                                    • Slide Number 70
                                                                                    • Slide Number 71
                                                                                    • Slide Number 72
                                                                                    • Slide Number 73
                                                                                    • DIC Management Goals
                                                                                    • DIC Management and Treatment
                                                                                    • DIC Management Strategies
                                                                                    • Anticoagulant Factor Concentrate Treatment
                                                                                    • Anticoagulant Factor Concentrate Treatment Trials
                                                                                    • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                    • D-dimer FDPs and DIC
                                                                                    • D-Dimer and FDPs in DIC
                                                                                    • Follow Up of DIC State of Disease
                                                                                    • FMD-Dimer in DIC Major Differences
                                                                                    • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                    • Slide Number 85
                                                                                    • Slide Number 86
                                                                                    • Comparing an Automated FM vs Manual FSP Test
                                                                                    • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                    • Slide Number 94
                                                                                    • Slide Number 95
                                                                                    • Slide Number 96
                                                                                    • Slide Number 97
                                                                                    • Slide Number 98
                                                                                    • Slide Number 99
                                                                                    • DIC Case Studies
                                                                                    • Case Study 1 - Presentation
                                                                                    • Case Study 1 ndash Lab Results
                                                                                    • Case Study 1 ndash Microscopy
                                                                                    • Case Study 1 ndash Diagnosis and Therapy
                                                                                    • Slide Number 105
                                                                                    • Slide Number 106
                                                                                    • Slide Number 107
                                                                                    • Slide Number 108
                                                                                    • Slide Number 109
                                                                                    • Slide Number 110
                                                                                    • Slide Number 111
                                                                                    • Slide Number 112
                                                                                    • Slide Number 113
                                                                                    • Slide Number 114
                                                                                    • Slide Number 115
                                                                                    • Slide Number 116
                                                                                    • Slide Number 117
                                                                                    • Slide Number 118
                                                                                    • Slide Number 119
                                                                                    • Slide Number 120
                                                                                    • Slide Number 121
                                                                                    • Slide Number 122
                                                                                    • Slide Number 123
                                                                                    • Slide Number 124
                                                                                    • Slide Number 125
                                                                                    • DIC Take Home Messages
                                                                                    • Slide Number 127
                                                                                    • Slide Number 128

                                                                                      Organ Failure in Severe Sepsis

                                                                                      Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure

                                                                                      Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51

                                                                                      Mechanism of DIC in Organ Failure

                                                                                      Underlying condition(sepsis trauma)

                                                                                      Cytokines

                                                                                      TF-mediatedactivation of coagulation

                                                                                      Depression of inhibitory systems

                                                                                      Reducesfibrinolysis

                                                                                      Fibrin deposition

                                                                                      Organ failure

                                                                                      Inadequate fibrin removal

                                                                                      Fibrinformation

                                                                                      Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )

                                                                                      Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705

                                                                                      Interaction of Inflammation and Coagulation in Sepsis

                                                                                      Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines

                                                                                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                      Mechanism of Multiple Organ Failure in DIC

                                                                                      Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

                                                                                      Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

                                                                                      lipopolysaccharides

                                                                                      cytokines

                                                                                      coagulation activation

                                                                                      mononuclear cell

                                                                                      tissue factor

                                                                                      Diverse and Opposing Effects of Thrombin

                                                                                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                      Coagulation and Fibrinolysis in DIC

                                                                                      Soluble fibrin Polymer

                                                                                      XIIIa

                                                                                      D-Dimer

                                                                                      E

                                                                                      Fibrin clot

                                                                                      Fibrin Degradation Products

                                                                                      Fibrinogen Thrombin

                                                                                      Fibrinogen Degradation

                                                                                      Products

                                                                                      D E

                                                                                      Plasmin

                                                                                      DFM + fibrinopeptides

                                                                                      Soluble FM ComplexesPre-throm

                                                                                      boticPost-throm

                                                                                      botic

                                                                                      Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

                                                                                      Mechanism of DIC

                                                                                      THROMBOSIS

                                                                                      Fibrin

                                                                                      Blood activationEndothelial lysisTF expression

                                                                                      BLEEDING

                                                                                      FDPs

                                                                                      D-Dimer

                                                                                      Plasmin

                                                                                      Pathophysiology of DIC

                                                                                      1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

                                                                                      thromboplastin influx of activated cells (monocytes macrophages)

                                                                                      Results in an intravascular deposition of fibrin

                                                                                      Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

                                                                                      Second step Consumption and depletion of coagulation factors inhibitors (Protein C

                                                                                      Protein S AT) and platelets Local fibrinolytic response

                                                                                      bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

                                                                                      FDP and D-Dimer

                                                                                      Bleeding

                                                                                      Pathophysiology of DIC - Mechanism

                                                                                      Systemic activation of coagulation

                                                                                      Intravasculardepositionof fibrin

                                                                                      Thrombosis of small and midsize vessels

                                                                                      and organ failure

                                                                                      Depletion of platelets and

                                                                                      coagulation factors

                                                                                      Bleeding

                                                                                      Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                                                                      Pathophysiology of DIC ndash 2 Types of Clinical pictures

                                                                                      Chronic = non - overt DICMay be unrecognized clinically

                                                                                      Acute = overt DIClife threatening bleedingor multiple organ failure

                                                                                      Sub-Acute and Non-Overt DIC Clinical Findings

                                                                                      Compensated non-overt DIC Steady low level or intermittent activation

                                                                                      bull Compensated by increased production of coagulation components and platelets

                                                                                      Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                                                                                      Risk of decompensation leading to overt DIC

                                                                                      Pathophysiology of Overt DIC

                                                                                      Massive activation of coagulation and fibrinolysis

                                                                                      Does not allow for compensatory efforts

                                                                                      Rapid depletion of coagulation factors inhibitors and platelets

                                                                                      Thrombosis multiple organ failures

                                                                                      Bleeding complications and shock

                                                                                      Physiopathology of DIC ndash Overt DIC Findings

                                                                                      Thrombin generation

                                                                                      Thrombosis

                                                                                      Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                                                                                      Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                                                                                      Plasmin generationHemorrhage

                                                                                      bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                                                                                      bull Tachycardia hypotension edema

                                                                                      Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                      Pathogenesis Pathways in DIC

                                                                                      Cytokines

                                                                                      TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                                                                                      fibrin inadequateformation fibrin removal

                                                                                      Fibrin deposition

                                                                                      Inflammation

                                                                                      Coagulation

                                                                                      Stago Celebrates Lab Week 2017

                                                                                      NA

                                                                                      Stago 247 Educational Webinar Sites

                                                                                      wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                                                                                      wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                                                                                      Stago Educational Apps

                                                                                      HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                                                                                      iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                                                                                      BREAK

                                                                                      Diagnostic and Management Approach for DIC

                                                                                      Diagnosis of DIC

                                                                                      Clinical diagnosis is obvious in cases of overt DIC

                                                                                      Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                                                                      Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                                                                      Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                                                                      Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                                                                      Important to recognize simultaneous formation of thrombin and plasmin

                                                                                      Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                      Lab Diagnosis of DIC ndash Screening Tests

                                                                                      Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                      Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                                                                      fibrinogen level) repeat testing assesses progression

                                                                                      Screening tests not clinically specific or sensitive for DIC

                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                      Laboratory Changes in Overt DIC

                                                                                      DIC Diagnostic Practices Over Time

                                                                                      Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                      British Journal of Haematology Overt DIC Score

                                                                                      Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                      ISTH Step by Step DIC Algorithm

                                                                                      Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                                                      US Based Validation of ISTH DIC Score

                                                                                      When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                      Differential Diagnosis in DIC

                                                                                      aHUS atypical hemolytic uremic syndrome

                                                                                      HUS hemolytic uremic syndrome

                                                                                      HIT heparin-induced thrombocytopenia

                                                                                      ITP immune thrombocytopenic purpura

                                                                                      TTP thrombotic thrombocytopenic purpura

                                                                                      DIC and MAHA

                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                      lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                                                      When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                                                      DIC Management Goals

                                                                                      Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                      Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                                                      DIC Management and Treatment

                                                                                      Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                      Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                                                      requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                                                      Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                                                      DIC Management Strategies

                                                                                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                      Anticoagulant Factor Concentrate Treatment

                                                                                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                      Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                                      Anticoagulant Factor Concentrate Treatment Trials

                                                                                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                      Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                                      Markers of Thrombin amp Plasmin Generation in DIC

                                                                                      D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                                      Cut-off value

                                                                                      Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                                      degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                                      D-dimer FDPs and DIC

                                                                                      D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                                      Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                                      Follow Up of DIC State of Disease

                                                                                      Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                                      Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                                      FMD-Dimer in DIC Major Differences

                                                                                      onset of thrombosis

                                                                                      days

                                                                                      Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                                      FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                                      D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                                      of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                                      0

                                                                                      20

                                                                                      40

                                                                                      60

                                                                                      80

                                                                                      100

                                                                                      94 85 90N = 62

                                                                                      Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                                      Positivity of Test Results ISTH Score and Disease State

                                                                                      Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                      Red bar positive for 2 points of DIC score

                                                                                      Pink bar positive for 1-2 points of DIC score

                                                                                      HT hematopoietic tumor

                                                                                      IF infection

                                                                                      SC solid cancer

                                                                                      Markers in Patients with or without DIC

                                                                                      Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                      HT hematopoietic tumorIF infectionSC solid cancer

                                                                                      Comparing an Automated FM vs Manual FSP Test

                                                                                      Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                      Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                      Automated (Mitsubishi) vs Automated (Stago)

                                                                                      In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                      Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                      In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                      In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                      In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                      Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                      No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                      Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                      Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                      Non Overt DIC Overt DIC

                                                                                      AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                      Trends in Markers of DIC for Different Patients

                                                                                      Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                      Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                      Trends in Markers of DIC for Different Patients

                                                                                      Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                      FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                      28 day outcome survival

                                                                                      28 day outcome death

                                                                                      Determination of Cutoffs of FM and D-dimer in DIC

                                                                                      Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                      Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                      Determination of Cutoffs of FM and D-dimer in DIC

                                                                                      Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                      Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                      DIC Case Studies

                                                                                      Case Study 1 - Presentation

                                                                                      18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                      Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                      WBC count 77 KμL 423 ndash 907 x KμL

                                                                                      RBC count 17 MμL 137 ndash 175 x MμL

                                                                                      Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                      Hematocrit 195 401 ndash 510

                                                                                      MCV 95 fL 790 ndash 922 fL

                                                                                      MPV 12 fL 94 ndash 124 fL

                                                                                      Platelet count 9 KμL 161 ndash 347 KμL

                                                                                      Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                      Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                      PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                      APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                      Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                      D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                      Case Study 1 ndash Microscopy

                                                                                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                      Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                      Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                      DIC due to TF release by APL blasts

                                                                                      Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                      Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                      20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                      Case Study 2 ndash Presentation

                                                                                      TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                      PT 30 sec 113 ndash 146 sec

                                                                                      APTT 75 sec 25 ndash 34 sec

                                                                                      D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                      Fibrinogen 92 mgdl 150-400 mgdl

                                                                                      pH 728 738 to 742

                                                                                      PaO2 570 mmHg 80-100 mmHg

                                                                                      WBC 33 times 103mm3 40-11 times 103mm3

                                                                                      ALT 111 IUL 0ndash34 IUL

                                                                                      AST 61 IUL 0ndash34 IUL

                                                                                      BUN 303 mgdL 08-13 mgdL

                                                                                      Case Study 2 ndash Lab Results

                                                                                      Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                      Case Study 2 ndash Diagnosis

                                                                                      60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                      Case Study 3 ndash Presentation

                                                                                      TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                      PT 228 sec 113 ndash 146 sec

                                                                                      APTT 45 sec 25 ndash 34 sec

                                                                                      D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                      Fibrinogen 82 mgdL 150-400 mgdL

                                                                                      FV Normal 70-120

                                                                                      FVII Normal 55-170

                                                                                      FVIII Normal 60-150

                                                                                      Protein C Normal 70-130

                                                                                      Hb 134 gdL 14-16 gdL

                                                                                      WBC 81 times 103mm3 40-11 times 103mm3

                                                                                      ALT 32 IUL 0ndash34 IUL

                                                                                      AST 28 IUL 0ndash34 IUL

                                                                                      BUN 09 mgdL 08-13 mgdL

                                                                                      Case Study 3 ndash Lab Results

                                                                                      Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                      Case Study 3 ndash Diagnosis and Therapy

                                                                                      Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                      Case Study 4 ndash Presentation

                                                                                      TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                      PT 28 sec 113 ndash 146 sec

                                                                                      APTT 71 sec 25 ndash 34 sec

                                                                                      D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                      Fibrinogen 92 mgdL 150-400 mgdl

                                                                                      FV Normal 70-120

                                                                                      FVII Normal 55-170

                                                                                      FVIII Normal 60-150

                                                                                      Protein C Normal 70-130

                                                                                      Hb 158 gdL 14-16 gdL

                                                                                      WBC 71 times 103mm3 40-11 times 103mm3

                                                                                      ALT 60 IUL 0ndash34 IUL

                                                                                      AST 47 IUL 0ndash34 IUL

                                                                                      BUN 38 mgdL 08-13 mgdL

                                                                                      Case Study 4 ndash Lab Results

                                                                                      Lyme disease with DICProvide antibiotics with supportive measures

                                                                                      Case Study 4 ndash Diagnosis

                                                                                      55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                      Case Study 5 ndash Presentation

                                                                                      Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                      Case Study 5 ndash Lab Results and Time Course

                                                                                      Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                      TEST RESULT REFERENCE RANGE

                                                                                      Platelet count 33 x 109L 150-450 x 109L

                                                                                      PT 215 sec 103 ndash 128 sec

                                                                                      APTT 44 sec 26 ndash 36 sec

                                                                                      D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                      Fibrinogen 34 mgdL 200-375 mgdl

                                                                                      FII FV FVIII Low Not reported (NR)

                                                                                      FVII FIX FX vWF Normal NR

                                                                                      Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                      DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                      dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                      (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                      (D) Illustration demonstrating repair

                                                                                      Case Study 5 ndash Diagnosis and Treatment

                                                                                      Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                      29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                      Case Study 6 ndash Presentation

                                                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                      Case Study 6 ndash Lab Results

                                                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                      TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                      PT 63 sec gt control 113 ndash 146 sec

                                                                                      INR 658 1 ndash 125

                                                                                      APTT 80 sec gt control 25 ndash 34 sec

                                                                                      D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                      Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                      Albumin 28 gdL NR

                                                                                      Hb 58 gdL NR

                                                                                      LDH 1196 UL NR

                                                                                      SGPT 144 IU NR

                                                                                      SGOT 88 IU NR

                                                                                      Bilirubin 32 mgdL NR

                                                                                      DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                      day postop

                                                                                      Case Study 6 ndash Diagnosis and Treatment

                                                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                      HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                      Case Study 6 ndash Discussion

                                                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                      44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                      Case Study 7 ndash Presentation

                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                      On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                      Case Study 7 ndash Presentation

                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                      Case Study 7 ndash Lab Results vs Time

                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                      Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                      Case Study 7 ndash Diagnosis and Treatment

                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                      On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                      Case Study 7 ndash Diagnosis and Treatment

                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                      DIC Take Home Messages

                                                                                      Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                      Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                      DIC

                                                                                      Thank you Questions

                                                                                      • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                      • Learning Objectives
                                                                                      • Slide Number 3
                                                                                      • Slide Number 4
                                                                                      • Slide Number 5
                                                                                      • Slide Number 6
                                                                                      • Slide Number 7
                                                                                      • Slide Number 8
                                                                                      • Wound Sealing
                                                                                      • The Three Steps of Hemostasis
                                                                                      • Vessel Wall
                                                                                      • Slide Number 12
                                                                                      • Slide Number 13
                                                                                      • Platelet Structure UnactivatedActivated
                                                                                      • Primary Hemostasis
                                                                                      • Primary Hemostasis Assays
                                                                                      • Slide Number 17
                                                                                      • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                      • Slide Number 19
                                                                                      • Coagulation factors
                                                                                      • Coagulation Assay Mechanisms
                                                                                      • Slide Number 22
                                                                                      • Fibrin Formation
                                                                                      • Slide Number 24
                                                                                      • Fibrinolysis Overview
                                                                                      • Fibrinolysis Overview
                                                                                      • Slide Number 27
                                                                                      • Fibrinolysis Releases D-dimers
                                                                                      • Basic Pathophysiology of DIC
                                                                                      • Disseminated Intravascular Coagulation (DIC)
                                                                                      • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                      • Clinical Conditions Associated With DIC
                                                                                      • Frequency of DIC in Selected Disease States
                                                                                      • Underlying Diseases in DIC Patients
                                                                                      • Slide Number 36
                                                                                      • Slide Number 37
                                                                                      • Slide Number 38
                                                                                      • Slide Number 39
                                                                                      • Pathophysiology of DIC
                                                                                      • Pathogenesis of DIC in Sepsis
                                                                                      • Host Response in Severe Sepsis
                                                                                      • Organ Failure in Severe Sepsis
                                                                                      • Mechanism of DIC in Organ Failure
                                                                                      • Interaction of Inflammation and Coagulation in Sepsis
                                                                                      • Slide Number 47
                                                                                      • Diverse and Opposing Effects of Thrombin
                                                                                      • Coagulation and Fibrinolysis in DIC
                                                                                      • Mechanism of DIC
                                                                                      • Pathophysiology of DIC
                                                                                      • Pathophysiology of DIC - Mechanism
                                                                                      • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                      • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                      • Pathophysiology of Overt DIC
                                                                                      • Physiopathology of DIC ndash Overt DIC Findings
                                                                                      • Slide Number 57
                                                                                      • Slide Number 58
                                                                                      • Slide Number 59
                                                                                      • Slide Number 60
                                                                                      • Slide Number 61
                                                                                      • BREAK
                                                                                      • Diagnostic and Management Approach for DIC
                                                                                      • Diagnosis of DIC
                                                                                      • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                      • Lab Diagnosis of DIC ndash Screening Tests
                                                                                      • Slide Number 67
                                                                                      • Slide Number 68
                                                                                      • British Journal of Haematology Overt DIC Score
                                                                                      • Slide Number 70
                                                                                      • Slide Number 71
                                                                                      • Slide Number 72
                                                                                      • Slide Number 73
                                                                                      • DIC Management Goals
                                                                                      • DIC Management and Treatment
                                                                                      • DIC Management Strategies
                                                                                      • Anticoagulant Factor Concentrate Treatment
                                                                                      • Anticoagulant Factor Concentrate Treatment Trials
                                                                                      • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                      • D-dimer FDPs and DIC
                                                                                      • D-Dimer and FDPs in DIC
                                                                                      • Follow Up of DIC State of Disease
                                                                                      • FMD-Dimer in DIC Major Differences
                                                                                      • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                      • Slide Number 85
                                                                                      • Slide Number 86
                                                                                      • Comparing an Automated FM vs Manual FSP Test
                                                                                      • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                      • Slide Number 94
                                                                                      • Slide Number 95
                                                                                      • Slide Number 96
                                                                                      • Slide Number 97
                                                                                      • Slide Number 98
                                                                                      • Slide Number 99
                                                                                      • DIC Case Studies
                                                                                      • Case Study 1 - Presentation
                                                                                      • Case Study 1 ndash Lab Results
                                                                                      • Case Study 1 ndash Microscopy
                                                                                      • Case Study 1 ndash Diagnosis and Therapy
                                                                                      • Slide Number 105
                                                                                      • Slide Number 106
                                                                                      • Slide Number 107
                                                                                      • Slide Number 108
                                                                                      • Slide Number 109
                                                                                      • Slide Number 110
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                                                                                      • Slide Number 112
                                                                                      • Slide Number 113
                                                                                      • Slide Number 114
                                                                                      • Slide Number 115
                                                                                      • Slide Number 116
                                                                                      • Slide Number 117
                                                                                      • Slide Number 118
                                                                                      • Slide Number 119
                                                                                      • Slide Number 120
                                                                                      • Slide Number 121
                                                                                      • Slide Number 122
                                                                                      • Slide Number 123
                                                                                      • Slide Number 124
                                                                                      • Slide Number 125
                                                                                      • DIC Take Home Messages
                                                                                      • Slide Number 127
                                                                                      • Slide Number 128

                                                                                        Mechanism of DIC in Organ Failure

                                                                                        Underlying condition(sepsis trauma)

                                                                                        Cytokines

                                                                                        TF-mediatedactivation of coagulation

                                                                                        Depression of inhibitory systems

                                                                                        Reducesfibrinolysis

                                                                                        Fibrin deposition

                                                                                        Organ failure

                                                                                        Inadequate fibrin removal

                                                                                        Fibrinformation

                                                                                        Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )

                                                                                        Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705

                                                                                        Interaction of Inflammation and Coagulation in Sepsis

                                                                                        Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines

                                                                                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                        Mechanism of Multiple Organ Failure in DIC

                                                                                        Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

                                                                                        Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

                                                                                        lipopolysaccharides

                                                                                        cytokines

                                                                                        coagulation activation

                                                                                        mononuclear cell

                                                                                        tissue factor

                                                                                        Diverse and Opposing Effects of Thrombin

                                                                                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                        Coagulation and Fibrinolysis in DIC

                                                                                        Soluble fibrin Polymer

                                                                                        XIIIa

                                                                                        D-Dimer

                                                                                        E

                                                                                        Fibrin clot

                                                                                        Fibrin Degradation Products

                                                                                        Fibrinogen Thrombin

                                                                                        Fibrinogen Degradation

                                                                                        Products

                                                                                        D E

                                                                                        Plasmin

                                                                                        DFM + fibrinopeptides

                                                                                        Soluble FM ComplexesPre-throm

                                                                                        boticPost-throm

                                                                                        botic

                                                                                        Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

                                                                                        Mechanism of DIC

                                                                                        THROMBOSIS

                                                                                        Fibrin

                                                                                        Blood activationEndothelial lysisTF expression

                                                                                        BLEEDING

                                                                                        FDPs

                                                                                        D-Dimer

                                                                                        Plasmin

                                                                                        Pathophysiology of DIC

                                                                                        1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

                                                                                        thromboplastin influx of activated cells (monocytes macrophages)

                                                                                        Results in an intravascular deposition of fibrin

                                                                                        Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

                                                                                        Second step Consumption and depletion of coagulation factors inhibitors (Protein C

                                                                                        Protein S AT) and platelets Local fibrinolytic response

                                                                                        bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

                                                                                        FDP and D-Dimer

                                                                                        Bleeding

                                                                                        Pathophysiology of DIC - Mechanism

                                                                                        Systemic activation of coagulation

                                                                                        Intravasculardepositionof fibrin

                                                                                        Thrombosis of small and midsize vessels

                                                                                        and organ failure

                                                                                        Depletion of platelets and

                                                                                        coagulation factors

                                                                                        Bleeding

                                                                                        Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                                                                        Pathophysiology of DIC ndash 2 Types of Clinical pictures

                                                                                        Chronic = non - overt DICMay be unrecognized clinically

                                                                                        Acute = overt DIClife threatening bleedingor multiple organ failure

                                                                                        Sub-Acute and Non-Overt DIC Clinical Findings

                                                                                        Compensated non-overt DIC Steady low level or intermittent activation

                                                                                        bull Compensated by increased production of coagulation components and platelets

                                                                                        Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                                                                                        Risk of decompensation leading to overt DIC

                                                                                        Pathophysiology of Overt DIC

                                                                                        Massive activation of coagulation and fibrinolysis

                                                                                        Does not allow for compensatory efforts

                                                                                        Rapid depletion of coagulation factors inhibitors and platelets

                                                                                        Thrombosis multiple organ failures

                                                                                        Bleeding complications and shock

                                                                                        Physiopathology of DIC ndash Overt DIC Findings

                                                                                        Thrombin generation

                                                                                        Thrombosis

                                                                                        Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                                                                                        Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                                                                                        Plasmin generationHemorrhage

                                                                                        bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                                                                                        bull Tachycardia hypotension edema

                                                                                        Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                        Pathogenesis Pathways in DIC

                                                                                        Cytokines

                                                                                        TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                                                                                        fibrin inadequateformation fibrin removal

                                                                                        Fibrin deposition

                                                                                        Inflammation

                                                                                        Coagulation

                                                                                        Stago Celebrates Lab Week 2017

                                                                                        NA

                                                                                        Stago 247 Educational Webinar Sites

                                                                                        wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                                                                                        wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                                                                                        Stago Educational Apps

                                                                                        HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                                                                                        iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                                                                                        BREAK

                                                                                        Diagnostic and Management Approach for DIC

                                                                                        Diagnosis of DIC

                                                                                        Clinical diagnosis is obvious in cases of overt DIC

                                                                                        Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                                                                        Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                                                                        Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                                                                        Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                                                                        Important to recognize simultaneous formation of thrombin and plasmin

                                                                                        Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                        Lab Diagnosis of DIC ndash Screening Tests

                                                                                        Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                        Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                                                                        fibrinogen level) repeat testing assesses progression

                                                                                        Screening tests not clinically specific or sensitive for DIC

                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                        Laboratory Changes in Overt DIC

                                                                                        DIC Diagnostic Practices Over Time

                                                                                        Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                        British Journal of Haematology Overt DIC Score

                                                                                        Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                        ISTH Step by Step DIC Algorithm

                                                                                        Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                                                        US Based Validation of ISTH DIC Score

                                                                                        When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                        Differential Diagnosis in DIC

                                                                                        aHUS atypical hemolytic uremic syndrome

                                                                                        HUS hemolytic uremic syndrome

                                                                                        HIT heparin-induced thrombocytopenia

                                                                                        ITP immune thrombocytopenic purpura

                                                                                        TTP thrombotic thrombocytopenic purpura

                                                                                        DIC and MAHA

                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                        lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                                                        When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                                                        DIC Management Goals

                                                                                        Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                        Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                                                        DIC Management and Treatment

                                                                                        Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                        Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                                                        requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                                                        Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                                                        DIC Management Strategies

                                                                                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                        Anticoagulant Factor Concentrate Treatment

                                                                                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                        Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                                        Anticoagulant Factor Concentrate Treatment Trials

                                                                                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                        Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                                        Markers of Thrombin amp Plasmin Generation in DIC

                                                                                        D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                                        Cut-off value

                                                                                        Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                                        degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                                        D-dimer FDPs and DIC

                                                                                        D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                                        Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                                        Follow Up of DIC State of Disease

                                                                                        Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                                        Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                                        FMD-Dimer in DIC Major Differences

                                                                                        onset of thrombosis

                                                                                        days

                                                                                        Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                                        FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                                        D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                                        of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                                        0

                                                                                        20

                                                                                        40

                                                                                        60

                                                                                        80

                                                                                        100

                                                                                        94 85 90N = 62

                                                                                        Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                                        Positivity of Test Results ISTH Score and Disease State

                                                                                        Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                        Red bar positive for 2 points of DIC score

                                                                                        Pink bar positive for 1-2 points of DIC score

                                                                                        HT hematopoietic tumor

                                                                                        IF infection

                                                                                        SC solid cancer

                                                                                        Markers in Patients with or without DIC

                                                                                        Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                        HT hematopoietic tumorIF infectionSC solid cancer

                                                                                        Comparing an Automated FM vs Manual FSP Test

                                                                                        Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                        Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                        Automated (Mitsubishi) vs Automated (Stago)

                                                                                        In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                        Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                        In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                        In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                        In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                        Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                        No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                        Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                        Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                        Non Overt DIC Overt DIC

                                                                                        AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                        Trends in Markers of DIC for Different Patients

                                                                                        Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                        Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                        Trends in Markers of DIC for Different Patients

                                                                                        Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                        FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                        28 day outcome survival

                                                                                        28 day outcome death

                                                                                        Determination of Cutoffs of FM and D-dimer in DIC

                                                                                        Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                        Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                        Determination of Cutoffs of FM and D-dimer in DIC

                                                                                        Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                        Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                        DIC Case Studies

                                                                                        Case Study 1 - Presentation

                                                                                        18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                        Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                        WBC count 77 KμL 423 ndash 907 x KμL

                                                                                        RBC count 17 MμL 137 ndash 175 x MμL

                                                                                        Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                        Hematocrit 195 401 ndash 510

                                                                                        MCV 95 fL 790 ndash 922 fL

                                                                                        MPV 12 fL 94 ndash 124 fL

                                                                                        Platelet count 9 KμL 161 ndash 347 KμL

                                                                                        Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                        Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                        PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                        APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                        Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                        D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                        Case Study 1 ndash Microscopy

                                                                                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                        Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                        Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                        DIC due to TF release by APL blasts

                                                                                        Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                        Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                        20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                        Case Study 2 ndash Presentation

                                                                                        TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                        PT 30 sec 113 ndash 146 sec

                                                                                        APTT 75 sec 25 ndash 34 sec

                                                                                        D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                        Fibrinogen 92 mgdl 150-400 mgdl

                                                                                        pH 728 738 to 742

                                                                                        PaO2 570 mmHg 80-100 mmHg

                                                                                        WBC 33 times 103mm3 40-11 times 103mm3

                                                                                        ALT 111 IUL 0ndash34 IUL

                                                                                        AST 61 IUL 0ndash34 IUL

                                                                                        BUN 303 mgdL 08-13 mgdL

                                                                                        Case Study 2 ndash Lab Results

                                                                                        Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                        Case Study 2 ndash Diagnosis

                                                                                        60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                        Case Study 3 ndash Presentation

                                                                                        TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                        PT 228 sec 113 ndash 146 sec

                                                                                        APTT 45 sec 25 ndash 34 sec

                                                                                        D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                        Fibrinogen 82 mgdL 150-400 mgdL

                                                                                        FV Normal 70-120

                                                                                        FVII Normal 55-170

                                                                                        FVIII Normal 60-150

                                                                                        Protein C Normal 70-130

                                                                                        Hb 134 gdL 14-16 gdL

                                                                                        WBC 81 times 103mm3 40-11 times 103mm3

                                                                                        ALT 32 IUL 0ndash34 IUL

                                                                                        AST 28 IUL 0ndash34 IUL

                                                                                        BUN 09 mgdL 08-13 mgdL

                                                                                        Case Study 3 ndash Lab Results

                                                                                        Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                        Case Study 3 ndash Diagnosis and Therapy

                                                                                        Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                        Case Study 4 ndash Presentation

                                                                                        TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                        PT 28 sec 113 ndash 146 sec

                                                                                        APTT 71 sec 25 ndash 34 sec

                                                                                        D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                        Fibrinogen 92 mgdL 150-400 mgdl

                                                                                        FV Normal 70-120

                                                                                        FVII Normal 55-170

                                                                                        FVIII Normal 60-150

                                                                                        Protein C Normal 70-130

                                                                                        Hb 158 gdL 14-16 gdL

                                                                                        WBC 71 times 103mm3 40-11 times 103mm3

                                                                                        ALT 60 IUL 0ndash34 IUL

                                                                                        AST 47 IUL 0ndash34 IUL

                                                                                        BUN 38 mgdL 08-13 mgdL

                                                                                        Case Study 4 ndash Lab Results

                                                                                        Lyme disease with DICProvide antibiotics with supportive measures

                                                                                        Case Study 4 ndash Diagnosis

                                                                                        55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                        Case Study 5 ndash Presentation

                                                                                        Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                        Case Study 5 ndash Lab Results and Time Course

                                                                                        Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                        TEST RESULT REFERENCE RANGE

                                                                                        Platelet count 33 x 109L 150-450 x 109L

                                                                                        PT 215 sec 103 ndash 128 sec

                                                                                        APTT 44 sec 26 ndash 36 sec

                                                                                        D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                        Fibrinogen 34 mgdL 200-375 mgdl

                                                                                        FII FV FVIII Low Not reported (NR)

                                                                                        FVII FIX FX vWF Normal NR

                                                                                        Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                        DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                        dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                        (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                        (D) Illustration demonstrating repair

                                                                                        Case Study 5 ndash Diagnosis and Treatment

                                                                                        Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                        29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                        Case Study 6 ndash Presentation

                                                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                        Case Study 6 ndash Lab Results

                                                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                        TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                        PT 63 sec gt control 113 ndash 146 sec

                                                                                        INR 658 1 ndash 125

                                                                                        APTT 80 sec gt control 25 ndash 34 sec

                                                                                        D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                        Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                        Albumin 28 gdL NR

                                                                                        Hb 58 gdL NR

                                                                                        LDH 1196 UL NR

                                                                                        SGPT 144 IU NR

                                                                                        SGOT 88 IU NR

                                                                                        Bilirubin 32 mgdL NR

                                                                                        DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                        day postop

                                                                                        Case Study 6 ndash Diagnosis and Treatment

                                                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                        HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                        Case Study 6 ndash Discussion

                                                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                        44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                        Case Study 7 ndash Presentation

                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                        On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                        Case Study 7 ndash Presentation

                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                        Case Study 7 ndash Lab Results vs Time

                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                        Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                        Case Study 7 ndash Diagnosis and Treatment

                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                        On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                        Case Study 7 ndash Diagnosis and Treatment

                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                        DIC Take Home Messages

                                                                                        Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                        Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                        DIC

                                                                                        Thank you Questions

                                                                                        • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                        • Learning Objectives
                                                                                        • Slide Number 3
                                                                                        • Slide Number 4
                                                                                        • Slide Number 5
                                                                                        • Slide Number 6
                                                                                        • Slide Number 7
                                                                                        • Slide Number 8
                                                                                        • Wound Sealing
                                                                                        • The Three Steps of Hemostasis
                                                                                        • Vessel Wall
                                                                                        • Slide Number 12
                                                                                        • Slide Number 13
                                                                                        • Platelet Structure UnactivatedActivated
                                                                                        • Primary Hemostasis
                                                                                        • Primary Hemostasis Assays
                                                                                        • Slide Number 17
                                                                                        • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                        • Slide Number 19
                                                                                        • Coagulation factors
                                                                                        • Coagulation Assay Mechanisms
                                                                                        • Slide Number 22
                                                                                        • Fibrin Formation
                                                                                        • Slide Number 24
                                                                                        • Fibrinolysis Overview
                                                                                        • Fibrinolysis Overview
                                                                                        • Slide Number 27
                                                                                        • Fibrinolysis Releases D-dimers
                                                                                        • Basic Pathophysiology of DIC
                                                                                        • Disseminated Intravascular Coagulation (DIC)
                                                                                        • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                        • Clinical Conditions Associated With DIC
                                                                                        • Frequency of DIC in Selected Disease States
                                                                                        • Underlying Diseases in DIC Patients
                                                                                        • Slide Number 36
                                                                                        • Slide Number 37
                                                                                        • Slide Number 38
                                                                                        • Slide Number 39
                                                                                        • Pathophysiology of DIC
                                                                                        • Pathogenesis of DIC in Sepsis
                                                                                        • Host Response in Severe Sepsis
                                                                                        • Organ Failure in Severe Sepsis
                                                                                        • Mechanism of DIC in Organ Failure
                                                                                        • Interaction of Inflammation and Coagulation in Sepsis
                                                                                        • Slide Number 47
                                                                                        • Diverse and Opposing Effects of Thrombin
                                                                                        • Coagulation and Fibrinolysis in DIC
                                                                                        • Mechanism of DIC
                                                                                        • Pathophysiology of DIC
                                                                                        • Pathophysiology of DIC - Mechanism
                                                                                        • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                        • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                        • Pathophysiology of Overt DIC
                                                                                        • Physiopathology of DIC ndash Overt DIC Findings
                                                                                        • Slide Number 57
                                                                                        • Slide Number 58
                                                                                        • Slide Number 59
                                                                                        • Slide Number 60
                                                                                        • Slide Number 61
                                                                                        • BREAK
                                                                                        • Diagnostic and Management Approach for DIC
                                                                                        • Diagnosis of DIC
                                                                                        • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                        • Lab Diagnosis of DIC ndash Screening Tests
                                                                                        • Slide Number 67
                                                                                        • Slide Number 68
                                                                                        • British Journal of Haematology Overt DIC Score
                                                                                        • Slide Number 70
                                                                                        • Slide Number 71
                                                                                        • Slide Number 72
                                                                                        • Slide Number 73
                                                                                        • DIC Management Goals
                                                                                        • DIC Management and Treatment
                                                                                        • DIC Management Strategies
                                                                                        • Anticoagulant Factor Concentrate Treatment
                                                                                        • Anticoagulant Factor Concentrate Treatment Trials
                                                                                        • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                        • D-dimer FDPs and DIC
                                                                                        • D-Dimer and FDPs in DIC
                                                                                        • Follow Up of DIC State of Disease
                                                                                        • FMD-Dimer in DIC Major Differences
                                                                                        • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                        • Slide Number 85
                                                                                        • Slide Number 86
                                                                                        • Comparing an Automated FM vs Manual FSP Test
                                                                                        • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                        • Slide Number 94
                                                                                        • Slide Number 95
                                                                                        • Slide Number 96
                                                                                        • Slide Number 97
                                                                                        • Slide Number 98
                                                                                        • Slide Number 99
                                                                                        • DIC Case Studies
                                                                                        • Case Study 1 - Presentation
                                                                                        • Case Study 1 ndash Lab Results
                                                                                        • Case Study 1 ndash Microscopy
                                                                                        • Case Study 1 ndash Diagnosis and Therapy
                                                                                        • Slide Number 105
                                                                                        • Slide Number 106
                                                                                        • Slide Number 107
                                                                                        • Slide Number 108
                                                                                        • Slide Number 109
                                                                                        • Slide Number 110
                                                                                        • Slide Number 111
                                                                                        • Slide Number 112
                                                                                        • Slide Number 113
                                                                                        • Slide Number 114
                                                                                        • Slide Number 115
                                                                                        • Slide Number 116
                                                                                        • Slide Number 117
                                                                                        • Slide Number 118
                                                                                        • Slide Number 119
                                                                                        • Slide Number 120
                                                                                        • Slide Number 121
                                                                                        • Slide Number 122
                                                                                        • Slide Number 123
                                                                                        • Slide Number 124
                                                                                        • Slide Number 125
                                                                                        • DIC Take Home Messages
                                                                                        • Slide Number 127
                                                                                        • Slide Number 128

                                                                                          Interaction of Inflammation and Coagulation in Sepsis

                                                                                          Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines

                                                                                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                          Mechanism of Multiple Organ Failure in DIC

                                                                                          Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

                                                                                          Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

                                                                                          lipopolysaccharides

                                                                                          cytokines

                                                                                          coagulation activation

                                                                                          mononuclear cell

                                                                                          tissue factor

                                                                                          Diverse and Opposing Effects of Thrombin

                                                                                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                          Coagulation and Fibrinolysis in DIC

                                                                                          Soluble fibrin Polymer

                                                                                          XIIIa

                                                                                          D-Dimer

                                                                                          E

                                                                                          Fibrin clot

                                                                                          Fibrin Degradation Products

                                                                                          Fibrinogen Thrombin

                                                                                          Fibrinogen Degradation

                                                                                          Products

                                                                                          D E

                                                                                          Plasmin

                                                                                          DFM + fibrinopeptides

                                                                                          Soluble FM ComplexesPre-throm

                                                                                          boticPost-throm

                                                                                          botic

                                                                                          Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

                                                                                          Mechanism of DIC

                                                                                          THROMBOSIS

                                                                                          Fibrin

                                                                                          Blood activationEndothelial lysisTF expression

                                                                                          BLEEDING

                                                                                          FDPs

                                                                                          D-Dimer

                                                                                          Plasmin

                                                                                          Pathophysiology of DIC

                                                                                          1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

                                                                                          thromboplastin influx of activated cells (monocytes macrophages)

                                                                                          Results in an intravascular deposition of fibrin

                                                                                          Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

                                                                                          Second step Consumption and depletion of coagulation factors inhibitors (Protein C

                                                                                          Protein S AT) and platelets Local fibrinolytic response

                                                                                          bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

                                                                                          FDP and D-Dimer

                                                                                          Bleeding

                                                                                          Pathophysiology of DIC - Mechanism

                                                                                          Systemic activation of coagulation

                                                                                          Intravasculardepositionof fibrin

                                                                                          Thrombosis of small and midsize vessels

                                                                                          and organ failure

                                                                                          Depletion of platelets and

                                                                                          coagulation factors

                                                                                          Bleeding

                                                                                          Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                                                                          Pathophysiology of DIC ndash 2 Types of Clinical pictures

                                                                                          Chronic = non - overt DICMay be unrecognized clinically

                                                                                          Acute = overt DIClife threatening bleedingor multiple organ failure

                                                                                          Sub-Acute and Non-Overt DIC Clinical Findings

                                                                                          Compensated non-overt DIC Steady low level or intermittent activation

                                                                                          bull Compensated by increased production of coagulation components and platelets

                                                                                          Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                                                                                          Risk of decompensation leading to overt DIC

                                                                                          Pathophysiology of Overt DIC

                                                                                          Massive activation of coagulation and fibrinolysis

                                                                                          Does not allow for compensatory efforts

                                                                                          Rapid depletion of coagulation factors inhibitors and platelets

                                                                                          Thrombosis multiple organ failures

                                                                                          Bleeding complications and shock

                                                                                          Physiopathology of DIC ndash Overt DIC Findings

                                                                                          Thrombin generation

                                                                                          Thrombosis

                                                                                          Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                                                                                          Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                                                                                          Plasmin generationHemorrhage

                                                                                          bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                                                                                          bull Tachycardia hypotension edema

                                                                                          Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                          Pathogenesis Pathways in DIC

                                                                                          Cytokines

                                                                                          TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                                                                                          fibrin inadequateformation fibrin removal

                                                                                          Fibrin deposition

                                                                                          Inflammation

                                                                                          Coagulation

                                                                                          Stago Celebrates Lab Week 2017

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                                                                                          Stago 247 Educational Webinar Sites

                                                                                          wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                                                                                          wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                                                                                          Stago Educational Apps

                                                                                          HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                                                                                          iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                                                                                          BREAK

                                                                                          Diagnostic and Management Approach for DIC

                                                                                          Diagnosis of DIC

                                                                                          Clinical diagnosis is obvious in cases of overt DIC

                                                                                          Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                                                                          Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                                                                          Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                                                                          Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                                                                          Important to recognize simultaneous formation of thrombin and plasmin

                                                                                          Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                          Lab Diagnosis of DIC ndash Screening Tests

                                                                                          Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                          Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                                                                          fibrinogen level) repeat testing assesses progression

                                                                                          Screening tests not clinically specific or sensitive for DIC

                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                          Laboratory Changes in Overt DIC

                                                                                          DIC Diagnostic Practices Over Time

                                                                                          Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                          British Journal of Haematology Overt DIC Score

                                                                                          Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                          ISTH Step by Step DIC Algorithm

                                                                                          Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                                                          US Based Validation of ISTH DIC Score

                                                                                          When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                          Differential Diagnosis in DIC

                                                                                          aHUS atypical hemolytic uremic syndrome

                                                                                          HUS hemolytic uremic syndrome

                                                                                          HIT heparin-induced thrombocytopenia

                                                                                          ITP immune thrombocytopenic purpura

                                                                                          TTP thrombotic thrombocytopenic purpura

                                                                                          DIC and MAHA

                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                          lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                                                          When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                                                          DIC Management Goals

                                                                                          Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                          Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                                                          DIC Management and Treatment

                                                                                          Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                          Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                                                          requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                                                          Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                                                          DIC Management Strategies

                                                                                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                          Anticoagulant Factor Concentrate Treatment

                                                                                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                          Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                                          Anticoagulant Factor Concentrate Treatment Trials

                                                                                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                          Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                                          Markers of Thrombin amp Plasmin Generation in DIC

                                                                                          D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                                          Cut-off value

                                                                                          Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                                          degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                                          D-dimer FDPs and DIC

                                                                                          D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                                          Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                                          Follow Up of DIC State of Disease

                                                                                          Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                                          Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                                          FMD-Dimer in DIC Major Differences

                                                                                          onset of thrombosis

                                                                                          days

                                                                                          Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                                          FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                                          D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                                          of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                                          0

                                                                                          20

                                                                                          40

                                                                                          60

                                                                                          80

                                                                                          100

                                                                                          94 85 90N = 62

                                                                                          Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                                          Positivity of Test Results ISTH Score and Disease State

                                                                                          Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                          Red bar positive for 2 points of DIC score

                                                                                          Pink bar positive for 1-2 points of DIC score

                                                                                          HT hematopoietic tumor

                                                                                          IF infection

                                                                                          SC solid cancer

                                                                                          Markers in Patients with or without DIC

                                                                                          Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                          HT hematopoietic tumorIF infectionSC solid cancer

                                                                                          Comparing an Automated FM vs Manual FSP Test

                                                                                          Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                          Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                          Automated (Mitsubishi) vs Automated (Stago)

                                                                                          In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                          Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                          In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                          In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                          In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                                          Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                          No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                          Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                                          Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                          Non Overt DIC Overt DIC

                                                                                          AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                          Trends in Markers of DIC for Different Patients

                                                                                          Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                          Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                          Trends in Markers of DIC for Different Patients

                                                                                          Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                          FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                          28 day outcome survival

                                                                                          28 day outcome death

                                                                                          Determination of Cutoffs of FM and D-dimer in DIC

                                                                                          Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                          Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                          Determination of Cutoffs of FM and D-dimer in DIC

                                                                                          Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                          Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                          DIC Case Studies

                                                                                          Case Study 1 - Presentation

                                                                                          18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                          Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                          WBC count 77 KμL 423 ndash 907 x KμL

                                                                                          RBC count 17 MμL 137 ndash 175 x MμL

                                                                                          Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                          Hematocrit 195 401 ndash 510

                                                                                          MCV 95 fL 790 ndash 922 fL

                                                                                          MPV 12 fL 94 ndash 124 fL

                                                                                          Platelet count 9 KμL 161 ndash 347 KμL

                                                                                          Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                          Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                          PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                          APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                          Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                          D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                          Case Study 1 ndash Microscopy

                                                                                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                          Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                          Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                          DIC due to TF release by APL blasts

                                                                                          Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                          Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                          20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                          Case Study 2 ndash Presentation

                                                                                          TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                          PT 30 sec 113 ndash 146 sec

                                                                                          APTT 75 sec 25 ndash 34 sec

                                                                                          D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                          Fibrinogen 92 mgdl 150-400 mgdl

                                                                                          pH 728 738 to 742

                                                                                          PaO2 570 mmHg 80-100 mmHg

                                                                                          WBC 33 times 103mm3 40-11 times 103mm3

                                                                                          ALT 111 IUL 0ndash34 IUL

                                                                                          AST 61 IUL 0ndash34 IUL

                                                                                          BUN 303 mgdL 08-13 mgdL

                                                                                          Case Study 2 ndash Lab Results

                                                                                          Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                          Case Study 2 ndash Diagnosis

                                                                                          60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                          Case Study 3 ndash Presentation

                                                                                          TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                          PT 228 sec 113 ndash 146 sec

                                                                                          APTT 45 sec 25 ndash 34 sec

                                                                                          D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                          Fibrinogen 82 mgdL 150-400 mgdL

                                                                                          FV Normal 70-120

                                                                                          FVII Normal 55-170

                                                                                          FVIII Normal 60-150

                                                                                          Protein C Normal 70-130

                                                                                          Hb 134 gdL 14-16 gdL

                                                                                          WBC 81 times 103mm3 40-11 times 103mm3

                                                                                          ALT 32 IUL 0ndash34 IUL

                                                                                          AST 28 IUL 0ndash34 IUL

                                                                                          BUN 09 mgdL 08-13 mgdL

                                                                                          Case Study 3 ndash Lab Results

                                                                                          Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                          Case Study 3 ndash Diagnosis and Therapy

                                                                                          Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                          Case Study 4 ndash Presentation

                                                                                          TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                          PT 28 sec 113 ndash 146 sec

                                                                                          APTT 71 sec 25 ndash 34 sec

                                                                                          D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                          Fibrinogen 92 mgdL 150-400 mgdl

                                                                                          FV Normal 70-120

                                                                                          FVII Normal 55-170

                                                                                          FVIII Normal 60-150

                                                                                          Protein C Normal 70-130

                                                                                          Hb 158 gdL 14-16 gdL

                                                                                          WBC 71 times 103mm3 40-11 times 103mm3

                                                                                          ALT 60 IUL 0ndash34 IUL

                                                                                          AST 47 IUL 0ndash34 IUL

                                                                                          BUN 38 mgdL 08-13 mgdL

                                                                                          Case Study 4 ndash Lab Results

                                                                                          Lyme disease with DICProvide antibiotics with supportive measures

                                                                                          Case Study 4 ndash Diagnosis

                                                                                          55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                          Case Study 5 ndash Presentation

                                                                                          Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                          Case Study 5 ndash Lab Results and Time Course

                                                                                          Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                          TEST RESULT REFERENCE RANGE

                                                                                          Platelet count 33 x 109L 150-450 x 109L

                                                                                          PT 215 sec 103 ndash 128 sec

                                                                                          APTT 44 sec 26 ndash 36 sec

                                                                                          D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                          Fibrinogen 34 mgdL 200-375 mgdl

                                                                                          FII FV FVIII Low Not reported (NR)

                                                                                          FVII FIX FX vWF Normal NR

                                                                                          Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                          DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                          dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                          (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                          (D) Illustration demonstrating repair

                                                                                          Case Study 5 ndash Diagnosis and Treatment

                                                                                          Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                          29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                          Case Study 6 ndash Presentation

                                                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                          Case Study 6 ndash Lab Results

                                                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                          TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                          PT 63 sec gt control 113 ndash 146 sec

                                                                                          INR 658 1 ndash 125

                                                                                          APTT 80 sec gt control 25 ndash 34 sec

                                                                                          D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                          Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                          Albumin 28 gdL NR

                                                                                          Hb 58 gdL NR

                                                                                          LDH 1196 UL NR

                                                                                          SGPT 144 IU NR

                                                                                          SGOT 88 IU NR

                                                                                          Bilirubin 32 mgdL NR

                                                                                          DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                          day postop

                                                                                          Case Study 6 ndash Diagnosis and Treatment

                                                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                          HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                          Case Study 6 ndash Discussion

                                                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                          44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                          Case Study 7 ndash Presentation

                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                          On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                          Case Study 7 ndash Presentation

                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                          Case Study 7 ndash Lab Results vs Time

                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                          Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                          Case Study 7 ndash Diagnosis and Treatment

                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                          On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                          Case Study 7 ndash Diagnosis and Treatment

                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                          DIC Take Home Messages

                                                                                          Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                          Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                          DIC

                                                                                          Thank you Questions

                                                                                          • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                          • Learning Objectives
                                                                                          • Slide Number 3
                                                                                          • Slide Number 4
                                                                                          • Slide Number 5
                                                                                          • Slide Number 6
                                                                                          • Slide Number 7
                                                                                          • Slide Number 8
                                                                                          • Wound Sealing
                                                                                          • The Three Steps of Hemostasis
                                                                                          • Vessel Wall
                                                                                          • Slide Number 12
                                                                                          • Slide Number 13
                                                                                          • Platelet Structure UnactivatedActivated
                                                                                          • Primary Hemostasis
                                                                                          • Primary Hemostasis Assays
                                                                                          • Slide Number 17
                                                                                          • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                          • Slide Number 19
                                                                                          • Coagulation factors
                                                                                          • Coagulation Assay Mechanisms
                                                                                          • Slide Number 22
                                                                                          • Fibrin Formation
                                                                                          • Slide Number 24
                                                                                          • Fibrinolysis Overview
                                                                                          • Fibrinolysis Overview
                                                                                          • Slide Number 27
                                                                                          • Fibrinolysis Releases D-dimers
                                                                                          • Basic Pathophysiology of DIC
                                                                                          • Disseminated Intravascular Coagulation (DIC)
                                                                                          • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                          • Clinical Conditions Associated With DIC
                                                                                          • Frequency of DIC in Selected Disease States
                                                                                          • Underlying Diseases in DIC Patients
                                                                                          • Slide Number 36
                                                                                          • Slide Number 37
                                                                                          • Slide Number 38
                                                                                          • Slide Number 39
                                                                                          • Pathophysiology of DIC
                                                                                          • Pathogenesis of DIC in Sepsis
                                                                                          • Host Response in Severe Sepsis
                                                                                          • Organ Failure in Severe Sepsis
                                                                                          • Mechanism of DIC in Organ Failure
                                                                                          • Interaction of Inflammation and Coagulation in Sepsis
                                                                                          • Slide Number 47
                                                                                          • Diverse and Opposing Effects of Thrombin
                                                                                          • Coagulation and Fibrinolysis in DIC
                                                                                          • Mechanism of DIC
                                                                                          • Pathophysiology of DIC
                                                                                          • Pathophysiology of DIC - Mechanism
                                                                                          • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                          • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                          • Pathophysiology of Overt DIC
                                                                                          • Physiopathology of DIC ndash Overt DIC Findings
                                                                                          • Slide Number 57
                                                                                          • Slide Number 58
                                                                                          • Slide Number 59
                                                                                          • Slide Number 60
                                                                                          • Slide Number 61
                                                                                          • BREAK
                                                                                          • Diagnostic and Management Approach for DIC
                                                                                          • Diagnosis of DIC
                                                                                          • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                          • Lab Diagnosis of DIC ndash Screening Tests
                                                                                          • Slide Number 67
                                                                                          • Slide Number 68
                                                                                          • British Journal of Haematology Overt DIC Score
                                                                                          • Slide Number 70
                                                                                          • Slide Number 71
                                                                                          • Slide Number 72
                                                                                          • Slide Number 73
                                                                                          • DIC Management Goals
                                                                                          • DIC Management and Treatment
                                                                                          • DIC Management Strategies
                                                                                          • Anticoagulant Factor Concentrate Treatment
                                                                                          • Anticoagulant Factor Concentrate Treatment Trials
                                                                                          • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                          • D-dimer FDPs and DIC
                                                                                          • D-Dimer and FDPs in DIC
                                                                                          • Follow Up of DIC State of Disease
                                                                                          • FMD-Dimer in DIC Major Differences
                                                                                          • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                          • Slide Number 85
                                                                                          • Slide Number 86
                                                                                          • Comparing an Automated FM vs Manual FSP Test
                                                                                          • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                          • Slide Number 94
                                                                                          • Slide Number 95
                                                                                          • Slide Number 96
                                                                                          • Slide Number 97
                                                                                          • Slide Number 98
                                                                                          • Slide Number 99
                                                                                          • DIC Case Studies
                                                                                          • Case Study 1 - Presentation
                                                                                          • Case Study 1 ndash Lab Results
                                                                                          • Case Study 1 ndash Microscopy
                                                                                          • Case Study 1 ndash Diagnosis and Therapy
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                                                                                          • DIC Take Home Messages
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                                                                                            Mechanism of Multiple Organ Failure in DIC

                                                                                            Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14

                                                                                            Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC

                                                                                            lipopolysaccharides

                                                                                            cytokines

                                                                                            coagulation activation

                                                                                            mononuclear cell

                                                                                            tissue factor

                                                                                            Diverse and Opposing Effects of Thrombin

                                                                                            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                            Coagulation and Fibrinolysis in DIC

                                                                                            Soluble fibrin Polymer

                                                                                            XIIIa

                                                                                            D-Dimer

                                                                                            E

                                                                                            Fibrin clot

                                                                                            Fibrin Degradation Products

                                                                                            Fibrinogen Thrombin

                                                                                            Fibrinogen Degradation

                                                                                            Products

                                                                                            D E

                                                                                            Plasmin

                                                                                            DFM + fibrinopeptides

                                                                                            Soluble FM ComplexesPre-throm

                                                                                            boticPost-throm

                                                                                            botic

                                                                                            Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

                                                                                            Mechanism of DIC

                                                                                            THROMBOSIS

                                                                                            Fibrin

                                                                                            Blood activationEndothelial lysisTF expression

                                                                                            BLEEDING

                                                                                            FDPs

                                                                                            D-Dimer

                                                                                            Plasmin

                                                                                            Pathophysiology of DIC

                                                                                            1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

                                                                                            thromboplastin influx of activated cells (monocytes macrophages)

                                                                                            Results in an intravascular deposition of fibrin

                                                                                            Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

                                                                                            Second step Consumption and depletion of coagulation factors inhibitors (Protein C

                                                                                            Protein S AT) and platelets Local fibrinolytic response

                                                                                            bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

                                                                                            FDP and D-Dimer

                                                                                            Bleeding

                                                                                            Pathophysiology of DIC - Mechanism

                                                                                            Systemic activation of coagulation

                                                                                            Intravasculardepositionof fibrin

                                                                                            Thrombosis of small and midsize vessels

                                                                                            and organ failure

                                                                                            Depletion of platelets and

                                                                                            coagulation factors

                                                                                            Bleeding

                                                                                            Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                                                                            Pathophysiology of DIC ndash 2 Types of Clinical pictures

                                                                                            Chronic = non - overt DICMay be unrecognized clinically

                                                                                            Acute = overt DIClife threatening bleedingor multiple organ failure

                                                                                            Sub-Acute and Non-Overt DIC Clinical Findings

                                                                                            Compensated non-overt DIC Steady low level or intermittent activation

                                                                                            bull Compensated by increased production of coagulation components and platelets

                                                                                            Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                                                                                            Risk of decompensation leading to overt DIC

                                                                                            Pathophysiology of Overt DIC

                                                                                            Massive activation of coagulation and fibrinolysis

                                                                                            Does not allow for compensatory efforts

                                                                                            Rapid depletion of coagulation factors inhibitors and platelets

                                                                                            Thrombosis multiple organ failures

                                                                                            Bleeding complications and shock

                                                                                            Physiopathology of DIC ndash Overt DIC Findings

                                                                                            Thrombin generation

                                                                                            Thrombosis

                                                                                            Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                                                                                            Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                                                                                            Plasmin generationHemorrhage

                                                                                            bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                                                                                            bull Tachycardia hypotension edema

                                                                                            Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                            Pathogenesis Pathways in DIC

                                                                                            Cytokines

                                                                                            TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                                                                                            fibrin inadequateformation fibrin removal

                                                                                            Fibrin deposition

                                                                                            Inflammation

                                                                                            Coagulation

                                                                                            Stago Celebrates Lab Week 2017

                                                                                            NA

                                                                                            Stago 247 Educational Webinar Sites

                                                                                            wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                                                                                            wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                                                                                            Stago Educational Apps

                                                                                            HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                                                                                            iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                                                                                            BREAK

                                                                                            Diagnostic and Management Approach for DIC

                                                                                            Diagnosis of DIC

                                                                                            Clinical diagnosis is obvious in cases of overt DIC

                                                                                            Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                                                                            Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                                                                            Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                                                                            Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                                                                            Important to recognize simultaneous formation of thrombin and plasmin

                                                                                            Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                            Lab Diagnosis of DIC ndash Screening Tests

                                                                                            Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                            Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                                                                            fibrinogen level) repeat testing assesses progression

                                                                                            Screening tests not clinically specific or sensitive for DIC

                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                            Laboratory Changes in Overt DIC

                                                                                            DIC Diagnostic Practices Over Time

                                                                                            Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                            British Journal of Haematology Overt DIC Score

                                                                                            Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                            ISTH Step by Step DIC Algorithm

                                                                                            Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                                                            US Based Validation of ISTH DIC Score

                                                                                            When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                            Differential Diagnosis in DIC

                                                                                            aHUS atypical hemolytic uremic syndrome

                                                                                            HUS hemolytic uremic syndrome

                                                                                            HIT heparin-induced thrombocytopenia

                                                                                            ITP immune thrombocytopenic purpura

                                                                                            TTP thrombotic thrombocytopenic purpura

                                                                                            DIC and MAHA

                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                            lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                                                            When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                                                            DIC Management Goals

                                                                                            Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                            Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                                                            DIC Management and Treatment

                                                                                            Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                            Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                                                            requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                                                            Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                                                            DIC Management Strategies

                                                                                            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                            Anticoagulant Factor Concentrate Treatment

                                                                                            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                            Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                                            Anticoagulant Factor Concentrate Treatment Trials

                                                                                            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                            Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                                            Markers of Thrombin amp Plasmin Generation in DIC

                                                                                            D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                                            Cut-off value

                                                                                            Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                                            degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                                            D-dimer FDPs and DIC

                                                                                            D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                                            Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                                            Follow Up of DIC State of Disease

                                                                                            Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                                            Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                                            FMD-Dimer in DIC Major Differences

                                                                                            onset of thrombosis

                                                                                            days

                                                                                            Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                                            FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                                            D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                                            of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                                            0

                                                                                            20

                                                                                            40

                                                                                            60

                                                                                            80

                                                                                            100

                                                                                            94 85 90N = 62

                                                                                            Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                                            Positivity of Test Results ISTH Score and Disease State

                                                                                            Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                            Red bar positive for 2 points of DIC score

                                                                                            Pink bar positive for 1-2 points of DIC score

                                                                                            HT hematopoietic tumor

                                                                                            IF infection

                                                                                            SC solid cancer

                                                                                            Markers in Patients with or without DIC

                                                                                            Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                            HT hematopoietic tumorIF infectionSC solid cancer

                                                                                            Comparing an Automated FM vs Manual FSP Test

                                                                                            Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                            Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                            Automated (Mitsubishi) vs Automated (Stago)

                                                                                            In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                            Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                            In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                            In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                            In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                                            Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                            No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                            Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                                            Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                            Non Overt DIC Overt DIC

                                                                                            AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                            Trends in Markers of DIC for Different Patients

                                                                                            Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                            Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                            Trends in Markers of DIC for Different Patients

                                                                                            Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                            FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                            28 day outcome survival

                                                                                            28 day outcome death

                                                                                            Determination of Cutoffs of FM and D-dimer in DIC

                                                                                            Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                            Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                            Determination of Cutoffs of FM and D-dimer in DIC

                                                                                            Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                            Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                            DIC Case Studies

                                                                                            Case Study 1 - Presentation

                                                                                            18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                            Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                            WBC count 77 KμL 423 ndash 907 x KμL

                                                                                            RBC count 17 MμL 137 ndash 175 x MμL

                                                                                            Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                            Hematocrit 195 401 ndash 510

                                                                                            MCV 95 fL 790 ndash 922 fL

                                                                                            MPV 12 fL 94 ndash 124 fL

                                                                                            Platelet count 9 KμL 161 ndash 347 KμL

                                                                                            Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                            Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                            PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                            APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                            Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                            D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                            Case Study 1 ndash Microscopy

                                                                                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                            Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                            Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                            DIC due to TF release by APL blasts

                                                                                            Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                            Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                            20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                            Case Study 2 ndash Presentation

                                                                                            TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                            PT 30 sec 113 ndash 146 sec

                                                                                            APTT 75 sec 25 ndash 34 sec

                                                                                            D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                            Fibrinogen 92 mgdl 150-400 mgdl

                                                                                            pH 728 738 to 742

                                                                                            PaO2 570 mmHg 80-100 mmHg

                                                                                            WBC 33 times 103mm3 40-11 times 103mm3

                                                                                            ALT 111 IUL 0ndash34 IUL

                                                                                            AST 61 IUL 0ndash34 IUL

                                                                                            BUN 303 mgdL 08-13 mgdL

                                                                                            Case Study 2 ndash Lab Results

                                                                                            Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                            Case Study 2 ndash Diagnosis

                                                                                            60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                            Case Study 3 ndash Presentation

                                                                                            TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                            PT 228 sec 113 ndash 146 sec

                                                                                            APTT 45 sec 25 ndash 34 sec

                                                                                            D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                            Fibrinogen 82 mgdL 150-400 mgdL

                                                                                            FV Normal 70-120

                                                                                            FVII Normal 55-170

                                                                                            FVIII Normal 60-150

                                                                                            Protein C Normal 70-130

                                                                                            Hb 134 gdL 14-16 gdL

                                                                                            WBC 81 times 103mm3 40-11 times 103mm3

                                                                                            ALT 32 IUL 0ndash34 IUL

                                                                                            AST 28 IUL 0ndash34 IUL

                                                                                            BUN 09 mgdL 08-13 mgdL

                                                                                            Case Study 3 ndash Lab Results

                                                                                            Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                            Case Study 3 ndash Diagnosis and Therapy

                                                                                            Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                            Case Study 4 ndash Presentation

                                                                                            TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                            PT 28 sec 113 ndash 146 sec

                                                                                            APTT 71 sec 25 ndash 34 sec

                                                                                            D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                            Fibrinogen 92 mgdL 150-400 mgdl

                                                                                            FV Normal 70-120

                                                                                            FVII Normal 55-170

                                                                                            FVIII Normal 60-150

                                                                                            Protein C Normal 70-130

                                                                                            Hb 158 gdL 14-16 gdL

                                                                                            WBC 71 times 103mm3 40-11 times 103mm3

                                                                                            ALT 60 IUL 0ndash34 IUL

                                                                                            AST 47 IUL 0ndash34 IUL

                                                                                            BUN 38 mgdL 08-13 mgdL

                                                                                            Case Study 4 ndash Lab Results

                                                                                            Lyme disease with DICProvide antibiotics with supportive measures

                                                                                            Case Study 4 ndash Diagnosis

                                                                                            55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                            Case Study 5 ndash Presentation

                                                                                            Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                            Case Study 5 ndash Lab Results and Time Course

                                                                                            Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                            TEST RESULT REFERENCE RANGE

                                                                                            Platelet count 33 x 109L 150-450 x 109L

                                                                                            PT 215 sec 103 ndash 128 sec

                                                                                            APTT 44 sec 26 ndash 36 sec

                                                                                            D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                            Fibrinogen 34 mgdL 200-375 mgdl

                                                                                            FII FV FVIII Low Not reported (NR)

                                                                                            FVII FIX FX vWF Normal NR

                                                                                            Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                            DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                            dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                            (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                            (D) Illustration demonstrating repair

                                                                                            Case Study 5 ndash Diagnosis and Treatment

                                                                                            Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                            29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                            Case Study 6 ndash Presentation

                                                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                            Case Study 6 ndash Lab Results

                                                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                            TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                            PT 63 sec gt control 113 ndash 146 sec

                                                                                            INR 658 1 ndash 125

                                                                                            APTT 80 sec gt control 25 ndash 34 sec

                                                                                            D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                            Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                            Albumin 28 gdL NR

                                                                                            Hb 58 gdL NR

                                                                                            LDH 1196 UL NR

                                                                                            SGPT 144 IU NR

                                                                                            SGOT 88 IU NR

                                                                                            Bilirubin 32 mgdL NR

                                                                                            DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                            day postop

                                                                                            Case Study 6 ndash Diagnosis and Treatment

                                                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                            HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                            Case Study 6 ndash Discussion

                                                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                            44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                            Case Study 7 ndash Presentation

                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                            On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                            Case Study 7 ndash Presentation

                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                            Case Study 7 ndash Lab Results vs Time

                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                            Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                            Case Study 7 ndash Diagnosis and Treatment

                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                            On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                            Case Study 7 ndash Diagnosis and Treatment

                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                            DIC Take Home Messages

                                                                                            Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                            Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                            DIC

                                                                                            Thank you Questions

                                                                                            • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                            • Learning Objectives
                                                                                            • Slide Number 3
                                                                                            • Slide Number 4
                                                                                            • Slide Number 5
                                                                                            • Slide Number 6
                                                                                            • Slide Number 7
                                                                                            • Slide Number 8
                                                                                            • Wound Sealing
                                                                                            • The Three Steps of Hemostasis
                                                                                            • Vessel Wall
                                                                                            • Slide Number 12
                                                                                            • Slide Number 13
                                                                                            • Platelet Structure UnactivatedActivated
                                                                                            • Primary Hemostasis
                                                                                            • Primary Hemostasis Assays
                                                                                            • Slide Number 17
                                                                                            • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                            • Slide Number 19
                                                                                            • Coagulation factors
                                                                                            • Coagulation Assay Mechanisms
                                                                                            • Slide Number 22
                                                                                            • Fibrin Formation
                                                                                            • Slide Number 24
                                                                                            • Fibrinolysis Overview
                                                                                            • Fibrinolysis Overview
                                                                                            • Slide Number 27
                                                                                            • Fibrinolysis Releases D-dimers
                                                                                            • Basic Pathophysiology of DIC
                                                                                            • Disseminated Intravascular Coagulation (DIC)
                                                                                            • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                            • Clinical Conditions Associated With DIC
                                                                                            • Frequency of DIC in Selected Disease States
                                                                                            • Underlying Diseases in DIC Patients
                                                                                            • Slide Number 36
                                                                                            • Slide Number 37
                                                                                            • Slide Number 38
                                                                                            • Slide Number 39
                                                                                            • Pathophysiology of DIC
                                                                                            • Pathogenesis of DIC in Sepsis
                                                                                            • Host Response in Severe Sepsis
                                                                                            • Organ Failure in Severe Sepsis
                                                                                            • Mechanism of DIC in Organ Failure
                                                                                            • Interaction of Inflammation and Coagulation in Sepsis
                                                                                            • Slide Number 47
                                                                                            • Diverse and Opposing Effects of Thrombin
                                                                                            • Coagulation and Fibrinolysis in DIC
                                                                                            • Mechanism of DIC
                                                                                            • Pathophysiology of DIC
                                                                                            • Pathophysiology of DIC - Mechanism
                                                                                            • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                            • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                            • Pathophysiology of Overt DIC
                                                                                            • Physiopathology of DIC ndash Overt DIC Findings
                                                                                            • Slide Number 57
                                                                                            • Slide Number 58
                                                                                            • Slide Number 59
                                                                                            • Slide Number 60
                                                                                            • Slide Number 61
                                                                                            • BREAK
                                                                                            • Diagnostic and Management Approach for DIC
                                                                                            • Diagnosis of DIC
                                                                                            • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                            • Lab Diagnosis of DIC ndash Screening Tests
                                                                                            • Slide Number 67
                                                                                            • Slide Number 68
                                                                                            • British Journal of Haematology Overt DIC Score
                                                                                            • Slide Number 70
                                                                                            • Slide Number 71
                                                                                            • Slide Number 72
                                                                                            • Slide Number 73
                                                                                            • DIC Management Goals
                                                                                            • DIC Management and Treatment
                                                                                            • DIC Management Strategies
                                                                                            • Anticoagulant Factor Concentrate Treatment
                                                                                            • Anticoagulant Factor Concentrate Treatment Trials
                                                                                            • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                            • D-dimer FDPs and DIC
                                                                                            • D-Dimer and FDPs in DIC
                                                                                            • Follow Up of DIC State of Disease
                                                                                            • FMD-Dimer in DIC Major Differences
                                                                                            • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                            • Slide Number 85
                                                                                            • Slide Number 86
                                                                                            • Comparing an Automated FM vs Manual FSP Test
                                                                                            • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                            • Slide Number 94
                                                                                            • Slide Number 95
                                                                                            • Slide Number 96
                                                                                            • Slide Number 97
                                                                                            • Slide Number 98
                                                                                            • Slide Number 99
                                                                                            • DIC Case Studies
                                                                                            • Case Study 1 - Presentation
                                                                                            • Case Study 1 ndash Lab Results
                                                                                            • Case Study 1 ndash Microscopy
                                                                                            • Case Study 1 ndash Diagnosis and Therapy
                                                                                            • Slide Number 105
                                                                                            • Slide Number 106
                                                                                            • Slide Number 107
                                                                                            • Slide Number 108
                                                                                            • Slide Number 109
                                                                                            • Slide Number 110
                                                                                            • Slide Number 111
                                                                                            • Slide Number 112
                                                                                            • Slide Number 113
                                                                                            • Slide Number 114
                                                                                            • Slide Number 115
                                                                                            • Slide Number 116
                                                                                            • Slide Number 117
                                                                                            • Slide Number 118
                                                                                            • Slide Number 119
                                                                                            • Slide Number 120
                                                                                            • Slide Number 121
                                                                                            • Slide Number 122
                                                                                            • Slide Number 123
                                                                                            • Slide Number 124
                                                                                            • Slide Number 125
                                                                                            • DIC Take Home Messages
                                                                                            • Slide Number 127
                                                                                            • Slide Number 128

                                                                                              lipopolysaccharides

                                                                                              cytokines

                                                                                              coagulation activation

                                                                                              mononuclear cell

                                                                                              tissue factor

                                                                                              Diverse and Opposing Effects of Thrombin

                                                                                              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                              Coagulation and Fibrinolysis in DIC

                                                                                              Soluble fibrin Polymer

                                                                                              XIIIa

                                                                                              D-Dimer

                                                                                              E

                                                                                              Fibrin clot

                                                                                              Fibrin Degradation Products

                                                                                              Fibrinogen Thrombin

                                                                                              Fibrinogen Degradation

                                                                                              Products

                                                                                              D E

                                                                                              Plasmin

                                                                                              DFM + fibrinopeptides

                                                                                              Soluble FM ComplexesPre-throm

                                                                                              boticPost-throm

                                                                                              botic

                                                                                              Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

                                                                                              Mechanism of DIC

                                                                                              THROMBOSIS

                                                                                              Fibrin

                                                                                              Blood activationEndothelial lysisTF expression

                                                                                              BLEEDING

                                                                                              FDPs

                                                                                              D-Dimer

                                                                                              Plasmin

                                                                                              Pathophysiology of DIC

                                                                                              1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

                                                                                              thromboplastin influx of activated cells (monocytes macrophages)

                                                                                              Results in an intravascular deposition of fibrin

                                                                                              Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

                                                                                              Second step Consumption and depletion of coagulation factors inhibitors (Protein C

                                                                                              Protein S AT) and platelets Local fibrinolytic response

                                                                                              bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

                                                                                              FDP and D-Dimer

                                                                                              Bleeding

                                                                                              Pathophysiology of DIC - Mechanism

                                                                                              Systemic activation of coagulation

                                                                                              Intravasculardepositionof fibrin

                                                                                              Thrombosis of small and midsize vessels

                                                                                              and organ failure

                                                                                              Depletion of platelets and

                                                                                              coagulation factors

                                                                                              Bleeding

                                                                                              Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                                                                              Pathophysiology of DIC ndash 2 Types of Clinical pictures

                                                                                              Chronic = non - overt DICMay be unrecognized clinically

                                                                                              Acute = overt DIClife threatening bleedingor multiple organ failure

                                                                                              Sub-Acute and Non-Overt DIC Clinical Findings

                                                                                              Compensated non-overt DIC Steady low level or intermittent activation

                                                                                              bull Compensated by increased production of coagulation components and platelets

                                                                                              Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                                                                                              Risk of decompensation leading to overt DIC

                                                                                              Pathophysiology of Overt DIC

                                                                                              Massive activation of coagulation and fibrinolysis

                                                                                              Does not allow for compensatory efforts

                                                                                              Rapid depletion of coagulation factors inhibitors and platelets

                                                                                              Thrombosis multiple organ failures

                                                                                              Bleeding complications and shock

                                                                                              Physiopathology of DIC ndash Overt DIC Findings

                                                                                              Thrombin generation

                                                                                              Thrombosis

                                                                                              Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                                                                                              Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                                                                                              Plasmin generationHemorrhage

                                                                                              bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                                                                                              bull Tachycardia hypotension edema

                                                                                              Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                              Pathogenesis Pathways in DIC

                                                                                              Cytokines

                                                                                              TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                                                                                              fibrin inadequateformation fibrin removal

                                                                                              Fibrin deposition

                                                                                              Inflammation

                                                                                              Coagulation

                                                                                              Stago Celebrates Lab Week 2017

                                                                                              NA

                                                                                              Stago 247 Educational Webinar Sites

                                                                                              wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                                                                                              wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                                                                                              Stago Educational Apps

                                                                                              HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                                                                                              iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                                                                                              BREAK

                                                                                              Diagnostic and Management Approach for DIC

                                                                                              Diagnosis of DIC

                                                                                              Clinical diagnosis is obvious in cases of overt DIC

                                                                                              Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                                                                              Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                                                                              Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                                                                              Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                                                                              Important to recognize simultaneous formation of thrombin and plasmin

                                                                                              Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                              Lab Diagnosis of DIC ndash Screening Tests

                                                                                              Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                              Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                                                                              fibrinogen level) repeat testing assesses progression

                                                                                              Screening tests not clinically specific or sensitive for DIC

                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                              Laboratory Changes in Overt DIC

                                                                                              DIC Diagnostic Practices Over Time

                                                                                              Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                              British Journal of Haematology Overt DIC Score

                                                                                              Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                              ISTH Step by Step DIC Algorithm

                                                                                              Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                                                              US Based Validation of ISTH DIC Score

                                                                                              When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                              Differential Diagnosis in DIC

                                                                                              aHUS atypical hemolytic uremic syndrome

                                                                                              HUS hemolytic uremic syndrome

                                                                                              HIT heparin-induced thrombocytopenia

                                                                                              ITP immune thrombocytopenic purpura

                                                                                              TTP thrombotic thrombocytopenic purpura

                                                                                              DIC and MAHA

                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                              lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                                                              When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                                                              DIC Management Goals

                                                                                              Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                              Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                                                              DIC Management and Treatment

                                                                                              Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                              Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                                                              requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                                                              Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                                                              DIC Management Strategies

                                                                                              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                              Anticoagulant Factor Concentrate Treatment

                                                                                              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                              Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                                              Anticoagulant Factor Concentrate Treatment Trials

                                                                                              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                              Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                                              Markers of Thrombin amp Plasmin Generation in DIC

                                                                                              D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                                              Cut-off value

                                                                                              Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                                              degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                                              D-dimer FDPs and DIC

                                                                                              D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                                              Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                                              Follow Up of DIC State of Disease

                                                                                              Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                                              Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                                              FMD-Dimer in DIC Major Differences

                                                                                              onset of thrombosis

                                                                                              days

                                                                                              Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                                              FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                                              D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                                              of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                                              0

                                                                                              20

                                                                                              40

                                                                                              60

                                                                                              80

                                                                                              100

                                                                                              94 85 90N = 62

                                                                                              Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                                              Positivity of Test Results ISTH Score and Disease State

                                                                                              Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                              Red bar positive for 2 points of DIC score

                                                                                              Pink bar positive for 1-2 points of DIC score

                                                                                              HT hematopoietic tumor

                                                                                              IF infection

                                                                                              SC solid cancer

                                                                                              Markers in Patients with or without DIC

                                                                                              Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                              HT hematopoietic tumorIF infectionSC solid cancer

                                                                                              Comparing an Automated FM vs Manual FSP Test

                                                                                              Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                              Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                              Automated (Mitsubishi) vs Automated (Stago)

                                                                                              In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                              Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                              In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                              In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                              In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                                              Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                              No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                              Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                                              Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                              Non Overt DIC Overt DIC

                                                                                              AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                              Trends in Markers of DIC for Different Patients

                                                                                              Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                              Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                              Trends in Markers of DIC for Different Patients

                                                                                              Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                              FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                              28 day outcome survival

                                                                                              28 day outcome death

                                                                                              Determination of Cutoffs of FM and D-dimer in DIC

                                                                                              Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                              Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                              Determination of Cutoffs of FM and D-dimer in DIC

                                                                                              Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                              Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                              DIC Case Studies

                                                                                              Case Study 1 - Presentation

                                                                                              18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                              Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                              WBC count 77 KμL 423 ndash 907 x KμL

                                                                                              RBC count 17 MμL 137 ndash 175 x MμL

                                                                                              Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                              Hematocrit 195 401 ndash 510

                                                                                              MCV 95 fL 790 ndash 922 fL

                                                                                              MPV 12 fL 94 ndash 124 fL

                                                                                              Platelet count 9 KμL 161 ndash 347 KμL

                                                                                              Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                              Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                              PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                              APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                              Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                              D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                              Case Study 1 ndash Microscopy

                                                                                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                              Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                              Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                              DIC due to TF release by APL blasts

                                                                                              Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                              Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                              20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                              Case Study 2 ndash Presentation

                                                                                              TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                              PT 30 sec 113 ndash 146 sec

                                                                                              APTT 75 sec 25 ndash 34 sec

                                                                                              D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                              Fibrinogen 92 mgdl 150-400 mgdl

                                                                                              pH 728 738 to 742

                                                                                              PaO2 570 mmHg 80-100 mmHg

                                                                                              WBC 33 times 103mm3 40-11 times 103mm3

                                                                                              ALT 111 IUL 0ndash34 IUL

                                                                                              AST 61 IUL 0ndash34 IUL

                                                                                              BUN 303 mgdL 08-13 mgdL

                                                                                              Case Study 2 ndash Lab Results

                                                                                              Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                              Case Study 2 ndash Diagnosis

                                                                                              60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                              Case Study 3 ndash Presentation

                                                                                              TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                              PT 228 sec 113 ndash 146 sec

                                                                                              APTT 45 sec 25 ndash 34 sec

                                                                                              D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                              Fibrinogen 82 mgdL 150-400 mgdL

                                                                                              FV Normal 70-120

                                                                                              FVII Normal 55-170

                                                                                              FVIII Normal 60-150

                                                                                              Protein C Normal 70-130

                                                                                              Hb 134 gdL 14-16 gdL

                                                                                              WBC 81 times 103mm3 40-11 times 103mm3

                                                                                              ALT 32 IUL 0ndash34 IUL

                                                                                              AST 28 IUL 0ndash34 IUL

                                                                                              BUN 09 mgdL 08-13 mgdL

                                                                                              Case Study 3 ndash Lab Results

                                                                                              Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                              Case Study 3 ndash Diagnosis and Therapy

                                                                                              Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                              Case Study 4 ndash Presentation

                                                                                              TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                              PT 28 sec 113 ndash 146 sec

                                                                                              APTT 71 sec 25 ndash 34 sec

                                                                                              D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                              Fibrinogen 92 mgdL 150-400 mgdl

                                                                                              FV Normal 70-120

                                                                                              FVII Normal 55-170

                                                                                              FVIII Normal 60-150

                                                                                              Protein C Normal 70-130

                                                                                              Hb 158 gdL 14-16 gdL

                                                                                              WBC 71 times 103mm3 40-11 times 103mm3

                                                                                              ALT 60 IUL 0ndash34 IUL

                                                                                              AST 47 IUL 0ndash34 IUL

                                                                                              BUN 38 mgdL 08-13 mgdL

                                                                                              Case Study 4 ndash Lab Results

                                                                                              Lyme disease with DICProvide antibiotics with supportive measures

                                                                                              Case Study 4 ndash Diagnosis

                                                                                              55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                              Case Study 5 ndash Presentation

                                                                                              Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                              Case Study 5 ndash Lab Results and Time Course

                                                                                              Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                              TEST RESULT REFERENCE RANGE

                                                                                              Platelet count 33 x 109L 150-450 x 109L

                                                                                              PT 215 sec 103 ndash 128 sec

                                                                                              APTT 44 sec 26 ndash 36 sec

                                                                                              D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                              Fibrinogen 34 mgdL 200-375 mgdl

                                                                                              FII FV FVIII Low Not reported (NR)

                                                                                              FVII FIX FX vWF Normal NR

                                                                                              Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                              DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                              dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                              (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                              (D) Illustration demonstrating repair

                                                                                              Case Study 5 ndash Diagnosis and Treatment

                                                                                              Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                              29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                              Case Study 6 ndash Presentation

                                                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                              Case Study 6 ndash Lab Results

                                                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                              TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                              PT 63 sec gt control 113 ndash 146 sec

                                                                                              INR 658 1 ndash 125

                                                                                              APTT 80 sec gt control 25 ndash 34 sec

                                                                                              D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                              Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                              Albumin 28 gdL NR

                                                                                              Hb 58 gdL NR

                                                                                              LDH 1196 UL NR

                                                                                              SGPT 144 IU NR

                                                                                              SGOT 88 IU NR

                                                                                              Bilirubin 32 mgdL NR

                                                                                              DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                              day postop

                                                                                              Case Study 6 ndash Diagnosis and Treatment

                                                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                              HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                              Case Study 6 ndash Discussion

                                                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                              44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                              Case Study 7 ndash Presentation

                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                              On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                              Case Study 7 ndash Presentation

                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                              Case Study 7 ndash Lab Results vs Time

                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                              Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                              Case Study 7 ndash Diagnosis and Treatment

                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                              On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                              Case Study 7 ndash Diagnosis and Treatment

                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                              DIC Take Home Messages

                                                                                              Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                              Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                              DIC

                                                                                              Thank you Questions

                                                                                              • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                              • Learning Objectives
                                                                                              • Slide Number 3
                                                                                              • Slide Number 4
                                                                                              • Slide Number 5
                                                                                              • Slide Number 6
                                                                                              • Slide Number 7
                                                                                              • Slide Number 8
                                                                                              • Wound Sealing
                                                                                              • The Three Steps of Hemostasis
                                                                                              • Vessel Wall
                                                                                              • Slide Number 12
                                                                                              • Slide Number 13
                                                                                              • Platelet Structure UnactivatedActivated
                                                                                              • Primary Hemostasis
                                                                                              • Primary Hemostasis Assays
                                                                                              • Slide Number 17
                                                                                              • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                              • Slide Number 19
                                                                                              • Coagulation factors
                                                                                              • Coagulation Assay Mechanisms
                                                                                              • Slide Number 22
                                                                                              • Fibrin Formation
                                                                                              • Slide Number 24
                                                                                              • Fibrinolysis Overview
                                                                                              • Fibrinolysis Overview
                                                                                              • Slide Number 27
                                                                                              • Fibrinolysis Releases D-dimers
                                                                                              • Basic Pathophysiology of DIC
                                                                                              • Disseminated Intravascular Coagulation (DIC)
                                                                                              • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                              • Clinical Conditions Associated With DIC
                                                                                              • Frequency of DIC in Selected Disease States
                                                                                              • Underlying Diseases in DIC Patients
                                                                                              • Slide Number 36
                                                                                              • Slide Number 37
                                                                                              • Slide Number 38
                                                                                              • Slide Number 39
                                                                                              • Pathophysiology of DIC
                                                                                              • Pathogenesis of DIC in Sepsis
                                                                                              • Host Response in Severe Sepsis
                                                                                              • Organ Failure in Severe Sepsis
                                                                                              • Mechanism of DIC in Organ Failure
                                                                                              • Interaction of Inflammation and Coagulation in Sepsis
                                                                                              • Slide Number 47
                                                                                              • Diverse and Opposing Effects of Thrombin
                                                                                              • Coagulation and Fibrinolysis in DIC
                                                                                              • Mechanism of DIC
                                                                                              • Pathophysiology of DIC
                                                                                              • Pathophysiology of DIC - Mechanism
                                                                                              • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                              • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                              • Pathophysiology of Overt DIC
                                                                                              • Physiopathology of DIC ndash Overt DIC Findings
                                                                                              • Slide Number 57
                                                                                              • Slide Number 58
                                                                                              • Slide Number 59
                                                                                              • Slide Number 60
                                                                                              • Slide Number 61
                                                                                              • BREAK
                                                                                              • Diagnostic and Management Approach for DIC
                                                                                              • Diagnosis of DIC
                                                                                              • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                              • Lab Diagnosis of DIC ndash Screening Tests
                                                                                              • Slide Number 67
                                                                                              • Slide Number 68
                                                                                              • British Journal of Haematology Overt DIC Score
                                                                                              • Slide Number 70
                                                                                              • Slide Number 71
                                                                                              • Slide Number 72
                                                                                              • Slide Number 73
                                                                                              • DIC Management Goals
                                                                                              • DIC Management and Treatment
                                                                                              • DIC Management Strategies
                                                                                              • Anticoagulant Factor Concentrate Treatment
                                                                                              • Anticoagulant Factor Concentrate Treatment Trials
                                                                                              • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                              • D-dimer FDPs and DIC
                                                                                              • D-Dimer and FDPs in DIC
                                                                                              • Follow Up of DIC State of Disease
                                                                                              • FMD-Dimer in DIC Major Differences
                                                                                              • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                              • Slide Number 85
                                                                                              • Slide Number 86
                                                                                              • Comparing an Automated FM vs Manual FSP Test
                                                                                              • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                              • Slide Number 94
                                                                                              • Slide Number 95
                                                                                              • Slide Number 96
                                                                                              • Slide Number 97
                                                                                              • Slide Number 98
                                                                                              • Slide Number 99
                                                                                              • DIC Case Studies
                                                                                              • Case Study 1 - Presentation
                                                                                              • Case Study 1 ndash Lab Results
                                                                                              • Case Study 1 ndash Microscopy
                                                                                              • Case Study 1 ndash Diagnosis and Therapy
                                                                                              • Slide Number 105
                                                                                              • Slide Number 106
                                                                                              • Slide Number 107
                                                                                              • Slide Number 108
                                                                                              • Slide Number 109
                                                                                              • Slide Number 110
                                                                                              • Slide Number 111
                                                                                              • Slide Number 112
                                                                                              • Slide Number 113
                                                                                              • Slide Number 114
                                                                                              • Slide Number 115
                                                                                              • Slide Number 116
                                                                                              • Slide Number 117
                                                                                              • Slide Number 118
                                                                                              • Slide Number 119
                                                                                              • Slide Number 120
                                                                                              • Slide Number 121
                                                                                              • Slide Number 122
                                                                                              • Slide Number 123
                                                                                              • Slide Number 124
                                                                                              • Slide Number 125
                                                                                              • DIC Take Home Messages
                                                                                              • Slide Number 127
                                                                                              • Slide Number 128

                                                                                                Diverse and Opposing Effects of Thrombin

                                                                                                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                Coagulation and Fibrinolysis in DIC

                                                                                                Soluble fibrin Polymer

                                                                                                XIIIa

                                                                                                D-Dimer

                                                                                                E

                                                                                                Fibrin clot

                                                                                                Fibrin Degradation Products

                                                                                                Fibrinogen Thrombin

                                                                                                Fibrinogen Degradation

                                                                                                Products

                                                                                                D E

                                                                                                Plasmin

                                                                                                DFM + fibrinopeptides

                                                                                                Soluble FM ComplexesPre-throm

                                                                                                boticPost-throm

                                                                                                botic

                                                                                                Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

                                                                                                Mechanism of DIC

                                                                                                THROMBOSIS

                                                                                                Fibrin

                                                                                                Blood activationEndothelial lysisTF expression

                                                                                                BLEEDING

                                                                                                FDPs

                                                                                                D-Dimer

                                                                                                Plasmin

                                                                                                Pathophysiology of DIC

                                                                                                1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

                                                                                                thromboplastin influx of activated cells (monocytes macrophages)

                                                                                                Results in an intravascular deposition of fibrin

                                                                                                Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

                                                                                                Second step Consumption and depletion of coagulation factors inhibitors (Protein C

                                                                                                Protein S AT) and platelets Local fibrinolytic response

                                                                                                bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

                                                                                                FDP and D-Dimer

                                                                                                Bleeding

                                                                                                Pathophysiology of DIC - Mechanism

                                                                                                Systemic activation of coagulation

                                                                                                Intravasculardepositionof fibrin

                                                                                                Thrombosis of small and midsize vessels

                                                                                                and organ failure

                                                                                                Depletion of platelets and

                                                                                                coagulation factors

                                                                                                Bleeding

                                                                                                Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                                                                                Pathophysiology of DIC ndash 2 Types of Clinical pictures

                                                                                                Chronic = non - overt DICMay be unrecognized clinically

                                                                                                Acute = overt DIClife threatening bleedingor multiple organ failure

                                                                                                Sub-Acute and Non-Overt DIC Clinical Findings

                                                                                                Compensated non-overt DIC Steady low level or intermittent activation

                                                                                                bull Compensated by increased production of coagulation components and platelets

                                                                                                Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                                                                                                Risk of decompensation leading to overt DIC

                                                                                                Pathophysiology of Overt DIC

                                                                                                Massive activation of coagulation and fibrinolysis

                                                                                                Does not allow for compensatory efforts

                                                                                                Rapid depletion of coagulation factors inhibitors and platelets

                                                                                                Thrombosis multiple organ failures

                                                                                                Bleeding complications and shock

                                                                                                Physiopathology of DIC ndash Overt DIC Findings

                                                                                                Thrombin generation

                                                                                                Thrombosis

                                                                                                Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                                                                                                Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                                                                                                Plasmin generationHemorrhage

                                                                                                bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                                                                                                bull Tachycardia hypotension edema

                                                                                                Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                Pathogenesis Pathways in DIC

                                                                                                Cytokines

                                                                                                TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                                                                                                fibrin inadequateformation fibrin removal

                                                                                                Fibrin deposition

                                                                                                Inflammation

                                                                                                Coagulation

                                                                                                Stago Celebrates Lab Week 2017

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                                                                                                Stago 247 Educational Webinar Sites

                                                                                                wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                                                                                                wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                                                                                                Stago Educational Apps

                                                                                                HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                                                                                                iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                                                                                                BREAK

                                                                                                Diagnostic and Management Approach for DIC

                                                                                                Diagnosis of DIC

                                                                                                Clinical diagnosis is obvious in cases of overt DIC

                                                                                                Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                                                                                Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                                                                                Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                                                                                Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                                                                                Important to recognize simultaneous formation of thrombin and plasmin

                                                                                                Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                                Lab Diagnosis of DIC ndash Screening Tests

                                                                                                Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                                Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                                                                                fibrinogen level) repeat testing assesses progression

                                                                                                Screening tests not clinically specific or sensitive for DIC

                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                Laboratory Changes in Overt DIC

                                                                                                DIC Diagnostic Practices Over Time

                                                                                                Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                British Journal of Haematology Overt DIC Score

                                                                                                Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                ISTH Step by Step DIC Algorithm

                                                                                                Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                                                                US Based Validation of ISTH DIC Score

                                                                                                When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                Differential Diagnosis in DIC

                                                                                                aHUS atypical hemolytic uremic syndrome

                                                                                                HUS hemolytic uremic syndrome

                                                                                                HIT heparin-induced thrombocytopenia

                                                                                                ITP immune thrombocytopenic purpura

                                                                                                TTP thrombotic thrombocytopenic purpura

                                                                                                DIC and MAHA

                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                                                                When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                                                                DIC Management Goals

                                                                                                Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                                                                DIC Management and Treatment

                                                                                                Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                                                                requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                                                                Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                                                                DIC Management Strategies

                                                                                                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                Anticoagulant Factor Concentrate Treatment

                                                                                                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                                                Anticoagulant Factor Concentrate Treatment Trials

                                                                                                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                                                Markers of Thrombin amp Plasmin Generation in DIC

                                                                                                D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                                                Cut-off value

                                                                                                Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                                                degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                                                D-dimer FDPs and DIC

                                                                                                D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                                                Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                                                Follow Up of DIC State of Disease

                                                                                                Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                                                Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                                                FMD-Dimer in DIC Major Differences

                                                                                                onset of thrombosis

                                                                                                days

                                                                                                Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                                                FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                                                D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                                                of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                                                0

                                                                                                20

                                                                                                40

                                                                                                60

                                                                                                80

                                                                                                100

                                                                                                94 85 90N = 62

                                                                                                Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                                                Positivity of Test Results ISTH Score and Disease State

                                                                                                Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                Red bar positive for 2 points of DIC score

                                                                                                Pink bar positive for 1-2 points of DIC score

                                                                                                HT hematopoietic tumor

                                                                                                IF infection

                                                                                                SC solid cancer

                                                                                                Markers in Patients with or without DIC

                                                                                                Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                HT hematopoietic tumorIF infectionSC solid cancer

                                                                                                Comparing an Automated FM vs Manual FSP Test

                                                                                                Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                                Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                                Automated (Mitsubishi) vs Automated (Stago)

                                                                                                In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                                Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                                Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                                Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                Non Overt DIC Overt DIC

                                                                                                AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                Trends in Markers of DIC for Different Patients

                                                                                                Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                Trends in Markers of DIC for Different Patients

                                                                                                Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                28 day outcome survival

                                                                                                28 day outcome death

                                                                                                Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                DIC Case Studies

                                                                                                Case Study 1 - Presentation

                                                                                                18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                Hematocrit 195 401 ndash 510

                                                                                                MCV 95 fL 790 ndash 922 fL

                                                                                                MPV 12 fL 94 ndash 124 fL

                                                                                                Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                Case Study 1 ndash Microscopy

                                                                                                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                DIC due to TF release by APL blasts

                                                                                                Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                Case Study 2 ndash Presentation

                                                                                                TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                PT 30 sec 113 ndash 146 sec

                                                                                                APTT 75 sec 25 ndash 34 sec

                                                                                                D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                pH 728 738 to 742

                                                                                                PaO2 570 mmHg 80-100 mmHg

                                                                                                WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                ALT 111 IUL 0ndash34 IUL

                                                                                                AST 61 IUL 0ndash34 IUL

                                                                                                BUN 303 mgdL 08-13 mgdL

                                                                                                Case Study 2 ndash Lab Results

                                                                                                Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                Case Study 2 ndash Diagnosis

                                                                                                60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                Case Study 3 ndash Presentation

                                                                                                TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                PT 228 sec 113 ndash 146 sec

                                                                                                APTT 45 sec 25 ndash 34 sec

                                                                                                D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                FV Normal 70-120

                                                                                                FVII Normal 55-170

                                                                                                FVIII Normal 60-150

                                                                                                Protein C Normal 70-130

                                                                                                Hb 134 gdL 14-16 gdL

                                                                                                WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                ALT 32 IUL 0ndash34 IUL

                                                                                                AST 28 IUL 0ndash34 IUL

                                                                                                BUN 09 mgdL 08-13 mgdL

                                                                                                Case Study 3 ndash Lab Results

                                                                                                Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                Case Study 3 ndash Diagnosis and Therapy

                                                                                                Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                Case Study 4 ndash Presentation

                                                                                                TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                PT 28 sec 113 ndash 146 sec

                                                                                                APTT 71 sec 25 ndash 34 sec

                                                                                                D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                FV Normal 70-120

                                                                                                FVII Normal 55-170

                                                                                                FVIII Normal 60-150

                                                                                                Protein C Normal 70-130

                                                                                                Hb 158 gdL 14-16 gdL

                                                                                                WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                ALT 60 IUL 0ndash34 IUL

                                                                                                AST 47 IUL 0ndash34 IUL

                                                                                                BUN 38 mgdL 08-13 mgdL

                                                                                                Case Study 4 ndash Lab Results

                                                                                                Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                Case Study 4 ndash Diagnosis

                                                                                                55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                Case Study 5 ndash Presentation

                                                                                                Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                Case Study 5 ndash Lab Results and Time Course

                                                                                                Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                TEST RESULT REFERENCE RANGE

                                                                                                Platelet count 33 x 109L 150-450 x 109L

                                                                                                PT 215 sec 103 ndash 128 sec

                                                                                                APTT 44 sec 26 ndash 36 sec

                                                                                                D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                FII FV FVIII Low Not reported (NR)

                                                                                                FVII FIX FX vWF Normal NR

                                                                                                Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                (D) Illustration demonstrating repair

                                                                                                Case Study 5 ndash Diagnosis and Treatment

                                                                                                Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                Case Study 6 ndash Presentation

                                                                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                Case Study 6 ndash Lab Results

                                                                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                PT 63 sec gt control 113 ndash 146 sec

                                                                                                INR 658 1 ndash 125

                                                                                                APTT 80 sec gt control 25 ndash 34 sec

                                                                                                D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                Albumin 28 gdL NR

                                                                                                Hb 58 gdL NR

                                                                                                LDH 1196 UL NR

                                                                                                SGPT 144 IU NR

                                                                                                SGOT 88 IU NR

                                                                                                Bilirubin 32 mgdL NR

                                                                                                DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                day postop

                                                                                                Case Study 6 ndash Diagnosis and Treatment

                                                                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                Case Study 6 ndash Discussion

                                                                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                Case Study 7 ndash Presentation

                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                Case Study 7 ndash Presentation

                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                Case Study 7 ndash Lab Results vs Time

                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                Case Study 7 ndash Diagnosis and Treatment

                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                Case Study 7 ndash Diagnosis and Treatment

                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                DIC Take Home Messages

                                                                                                Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                DIC

                                                                                                Thank you Questions

                                                                                                • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                • Learning Objectives
                                                                                                • Slide Number 3
                                                                                                • Slide Number 4
                                                                                                • Slide Number 5
                                                                                                • Slide Number 6
                                                                                                • Slide Number 7
                                                                                                • Slide Number 8
                                                                                                • Wound Sealing
                                                                                                • The Three Steps of Hemostasis
                                                                                                • Vessel Wall
                                                                                                • Slide Number 12
                                                                                                • Slide Number 13
                                                                                                • Platelet Structure UnactivatedActivated
                                                                                                • Primary Hemostasis
                                                                                                • Primary Hemostasis Assays
                                                                                                • Slide Number 17
                                                                                                • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                • Slide Number 19
                                                                                                • Coagulation factors
                                                                                                • Coagulation Assay Mechanisms
                                                                                                • Slide Number 22
                                                                                                • Fibrin Formation
                                                                                                • Slide Number 24
                                                                                                • Fibrinolysis Overview
                                                                                                • Fibrinolysis Overview
                                                                                                • Slide Number 27
                                                                                                • Fibrinolysis Releases D-dimers
                                                                                                • Basic Pathophysiology of DIC
                                                                                                • Disseminated Intravascular Coagulation (DIC)
                                                                                                • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                • Clinical Conditions Associated With DIC
                                                                                                • Frequency of DIC in Selected Disease States
                                                                                                • Underlying Diseases in DIC Patients
                                                                                                • Slide Number 36
                                                                                                • Slide Number 37
                                                                                                • Slide Number 38
                                                                                                • Slide Number 39
                                                                                                • Pathophysiology of DIC
                                                                                                • Pathogenesis of DIC in Sepsis
                                                                                                • Host Response in Severe Sepsis
                                                                                                • Organ Failure in Severe Sepsis
                                                                                                • Mechanism of DIC in Organ Failure
                                                                                                • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                • Slide Number 47
                                                                                                • Diverse and Opposing Effects of Thrombin
                                                                                                • Coagulation and Fibrinolysis in DIC
                                                                                                • Mechanism of DIC
                                                                                                • Pathophysiology of DIC
                                                                                                • Pathophysiology of DIC - Mechanism
                                                                                                • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                • Pathophysiology of Overt DIC
                                                                                                • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                • Slide Number 57
                                                                                                • Slide Number 58
                                                                                                • Slide Number 59
                                                                                                • Slide Number 60
                                                                                                • Slide Number 61
                                                                                                • BREAK
                                                                                                • Diagnostic and Management Approach for DIC
                                                                                                • Diagnosis of DIC
                                                                                                • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                • Slide Number 67
                                                                                                • Slide Number 68
                                                                                                • British Journal of Haematology Overt DIC Score
                                                                                                • Slide Number 70
                                                                                                • Slide Number 71
                                                                                                • Slide Number 72
                                                                                                • Slide Number 73
                                                                                                • DIC Management Goals
                                                                                                • DIC Management and Treatment
                                                                                                • DIC Management Strategies
                                                                                                • Anticoagulant Factor Concentrate Treatment
                                                                                                • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                • D-dimer FDPs and DIC
                                                                                                • D-Dimer and FDPs in DIC
                                                                                                • Follow Up of DIC State of Disease
                                                                                                • FMD-Dimer in DIC Major Differences
                                                                                                • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                • Slide Number 85
                                                                                                • Slide Number 86
                                                                                                • Comparing an Automated FM vs Manual FSP Test
                                                                                                • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                • Slide Number 94
                                                                                                • Slide Number 95
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                                                                                                • Slide Number 97
                                                                                                • Slide Number 98
                                                                                                • Slide Number 99
                                                                                                • DIC Case Studies
                                                                                                • Case Study 1 - Presentation
                                                                                                • Case Study 1 ndash Lab Results
                                                                                                • Case Study 1 ndash Microscopy
                                                                                                • Case Study 1 ndash Diagnosis and Therapy
                                                                                                • Slide Number 105
                                                                                                • Slide Number 106
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                                                                                                • Slide Number 124
                                                                                                • Slide Number 125
                                                                                                • DIC Take Home Messages
                                                                                                • Slide Number 127
                                                                                                • Slide Number 128

                                                                                                  Coagulation and Fibrinolysis in DIC

                                                                                                  Soluble fibrin Polymer

                                                                                                  XIIIa

                                                                                                  D-Dimer

                                                                                                  E

                                                                                                  Fibrin clot

                                                                                                  Fibrin Degradation Products

                                                                                                  Fibrinogen Thrombin

                                                                                                  Fibrinogen Degradation

                                                                                                  Products

                                                                                                  D E

                                                                                                  Plasmin

                                                                                                  DFM + fibrinopeptides

                                                                                                  Soluble FM ComplexesPre-throm

                                                                                                  boticPost-throm

                                                                                                  botic

                                                                                                  Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8

                                                                                                  Mechanism of DIC

                                                                                                  THROMBOSIS

                                                                                                  Fibrin

                                                                                                  Blood activationEndothelial lysisTF expression

                                                                                                  BLEEDING

                                                                                                  FDPs

                                                                                                  D-Dimer

                                                                                                  Plasmin

                                                                                                  Pathophysiology of DIC

                                                                                                  1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

                                                                                                  thromboplastin influx of activated cells (monocytes macrophages)

                                                                                                  Results in an intravascular deposition of fibrin

                                                                                                  Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

                                                                                                  Second step Consumption and depletion of coagulation factors inhibitors (Protein C

                                                                                                  Protein S AT) and platelets Local fibrinolytic response

                                                                                                  bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

                                                                                                  FDP and D-Dimer

                                                                                                  Bleeding

                                                                                                  Pathophysiology of DIC - Mechanism

                                                                                                  Systemic activation of coagulation

                                                                                                  Intravasculardepositionof fibrin

                                                                                                  Thrombosis of small and midsize vessels

                                                                                                  and organ failure

                                                                                                  Depletion of platelets and

                                                                                                  coagulation factors

                                                                                                  Bleeding

                                                                                                  Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                                                                                  Pathophysiology of DIC ndash 2 Types of Clinical pictures

                                                                                                  Chronic = non - overt DICMay be unrecognized clinically

                                                                                                  Acute = overt DIClife threatening bleedingor multiple organ failure

                                                                                                  Sub-Acute and Non-Overt DIC Clinical Findings

                                                                                                  Compensated non-overt DIC Steady low level or intermittent activation

                                                                                                  bull Compensated by increased production of coagulation components and platelets

                                                                                                  Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                                                                                                  Risk of decompensation leading to overt DIC

                                                                                                  Pathophysiology of Overt DIC

                                                                                                  Massive activation of coagulation and fibrinolysis

                                                                                                  Does not allow for compensatory efforts

                                                                                                  Rapid depletion of coagulation factors inhibitors and platelets

                                                                                                  Thrombosis multiple organ failures

                                                                                                  Bleeding complications and shock

                                                                                                  Physiopathology of DIC ndash Overt DIC Findings

                                                                                                  Thrombin generation

                                                                                                  Thrombosis

                                                                                                  Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                                                                                                  Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                                                                                                  Plasmin generationHemorrhage

                                                                                                  bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                                                                                                  bull Tachycardia hypotension edema

                                                                                                  Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                  Pathogenesis Pathways in DIC

                                                                                                  Cytokines

                                                                                                  TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                                                                                                  fibrin inadequateformation fibrin removal

                                                                                                  Fibrin deposition

                                                                                                  Inflammation

                                                                                                  Coagulation

                                                                                                  Stago Celebrates Lab Week 2017

                                                                                                  NA

                                                                                                  Stago 247 Educational Webinar Sites

                                                                                                  wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                                                                                                  wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                                                                                                  Stago Educational Apps

                                                                                                  HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                                                                                                  iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                                                                                                  BREAK

                                                                                                  Diagnostic and Management Approach for DIC

                                                                                                  Diagnosis of DIC

                                                                                                  Clinical diagnosis is obvious in cases of overt DIC

                                                                                                  Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                                                                                  Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                                                                                  Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                                                                                  Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                                                                                  Important to recognize simultaneous formation of thrombin and plasmin

                                                                                                  Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                                  Lab Diagnosis of DIC ndash Screening Tests

                                                                                                  Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                                  Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                                                                                  fibrinogen level) repeat testing assesses progression

                                                                                                  Screening tests not clinically specific or sensitive for DIC

                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                  Laboratory Changes in Overt DIC

                                                                                                  DIC Diagnostic Practices Over Time

                                                                                                  Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                  British Journal of Haematology Overt DIC Score

                                                                                                  Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                  ISTH Step by Step DIC Algorithm

                                                                                                  Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                                                                  US Based Validation of ISTH DIC Score

                                                                                                  When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                  Differential Diagnosis in DIC

                                                                                                  aHUS atypical hemolytic uremic syndrome

                                                                                                  HUS hemolytic uremic syndrome

                                                                                                  HIT heparin-induced thrombocytopenia

                                                                                                  ITP immune thrombocytopenic purpura

                                                                                                  TTP thrombotic thrombocytopenic purpura

                                                                                                  DIC and MAHA

                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                  lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                                                                  When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                                                                  DIC Management Goals

                                                                                                  Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                  Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                                                                  DIC Management and Treatment

                                                                                                  Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                  Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                                                                  requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                                                                  Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                                                                  DIC Management Strategies

                                                                                                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                  Anticoagulant Factor Concentrate Treatment

                                                                                                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                  Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                                                  Anticoagulant Factor Concentrate Treatment Trials

                                                                                                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                  Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                                                  Markers of Thrombin amp Plasmin Generation in DIC

                                                                                                  D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                                                  Cut-off value

                                                                                                  Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                                                  degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                                                  D-dimer FDPs and DIC

                                                                                                  D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                                                  Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                                                  Follow Up of DIC State of Disease

                                                                                                  Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                                                  Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                                                  FMD-Dimer in DIC Major Differences

                                                                                                  onset of thrombosis

                                                                                                  days

                                                                                                  Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                                                  FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                                                  D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                                                  of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                                                  0

                                                                                                  20

                                                                                                  40

                                                                                                  60

                                                                                                  80

                                                                                                  100

                                                                                                  94 85 90N = 62

                                                                                                  Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                                                  Positivity of Test Results ISTH Score and Disease State

                                                                                                  Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                  Red bar positive for 2 points of DIC score

                                                                                                  Pink bar positive for 1-2 points of DIC score

                                                                                                  HT hematopoietic tumor

                                                                                                  IF infection

                                                                                                  SC solid cancer

                                                                                                  Markers in Patients with or without DIC

                                                                                                  Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                  HT hematopoietic tumorIF infectionSC solid cancer

                                                                                                  Comparing an Automated FM vs Manual FSP Test

                                                                                                  Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                                  Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                                  Automated (Mitsubishi) vs Automated (Stago)

                                                                                                  In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                                  Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                  In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                  In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                  In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                                  Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                  No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                  Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                                  Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                  Non Overt DIC Overt DIC

                                                                                                  AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                  Trends in Markers of DIC for Different Patients

                                                                                                  Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                  Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                  Trends in Markers of DIC for Different Patients

                                                                                                  Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                  FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                  28 day outcome survival

                                                                                                  28 day outcome death

                                                                                                  Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                  Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                  Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                  Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                  Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                  Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                  DIC Case Studies

                                                                                                  Case Study 1 - Presentation

                                                                                                  18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                  Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                  WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                  RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                  Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                  Hematocrit 195 401 ndash 510

                                                                                                  MCV 95 fL 790 ndash 922 fL

                                                                                                  MPV 12 fL 94 ndash 124 fL

                                                                                                  Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                  Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                  Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                  PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                  APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                  Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                  D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                  Case Study 1 ndash Microscopy

                                                                                                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                  Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                  Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                  DIC due to TF release by APL blasts

                                                                                                  Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                  Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                  20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                  Case Study 2 ndash Presentation

                                                                                                  TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                  PT 30 sec 113 ndash 146 sec

                                                                                                  APTT 75 sec 25 ndash 34 sec

                                                                                                  D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                  Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                  pH 728 738 to 742

                                                                                                  PaO2 570 mmHg 80-100 mmHg

                                                                                                  WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                  ALT 111 IUL 0ndash34 IUL

                                                                                                  AST 61 IUL 0ndash34 IUL

                                                                                                  BUN 303 mgdL 08-13 mgdL

                                                                                                  Case Study 2 ndash Lab Results

                                                                                                  Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                  Case Study 2 ndash Diagnosis

                                                                                                  60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                  Case Study 3 ndash Presentation

                                                                                                  TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                  PT 228 sec 113 ndash 146 sec

                                                                                                  APTT 45 sec 25 ndash 34 sec

                                                                                                  D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                  Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                  FV Normal 70-120

                                                                                                  FVII Normal 55-170

                                                                                                  FVIII Normal 60-150

                                                                                                  Protein C Normal 70-130

                                                                                                  Hb 134 gdL 14-16 gdL

                                                                                                  WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                  ALT 32 IUL 0ndash34 IUL

                                                                                                  AST 28 IUL 0ndash34 IUL

                                                                                                  BUN 09 mgdL 08-13 mgdL

                                                                                                  Case Study 3 ndash Lab Results

                                                                                                  Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                  Case Study 3 ndash Diagnosis and Therapy

                                                                                                  Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                  Case Study 4 ndash Presentation

                                                                                                  TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                  PT 28 sec 113 ndash 146 sec

                                                                                                  APTT 71 sec 25 ndash 34 sec

                                                                                                  D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                  Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                  FV Normal 70-120

                                                                                                  FVII Normal 55-170

                                                                                                  FVIII Normal 60-150

                                                                                                  Protein C Normal 70-130

                                                                                                  Hb 158 gdL 14-16 gdL

                                                                                                  WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                  ALT 60 IUL 0ndash34 IUL

                                                                                                  AST 47 IUL 0ndash34 IUL

                                                                                                  BUN 38 mgdL 08-13 mgdL

                                                                                                  Case Study 4 ndash Lab Results

                                                                                                  Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                  Case Study 4 ndash Diagnosis

                                                                                                  55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                  Case Study 5 ndash Presentation

                                                                                                  Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                  Case Study 5 ndash Lab Results and Time Course

                                                                                                  Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                  TEST RESULT REFERENCE RANGE

                                                                                                  Platelet count 33 x 109L 150-450 x 109L

                                                                                                  PT 215 sec 103 ndash 128 sec

                                                                                                  APTT 44 sec 26 ndash 36 sec

                                                                                                  D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                  Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                  FII FV FVIII Low Not reported (NR)

                                                                                                  FVII FIX FX vWF Normal NR

                                                                                                  Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                  DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                  dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                  (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                  (D) Illustration demonstrating repair

                                                                                                  Case Study 5 ndash Diagnosis and Treatment

                                                                                                  Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                  29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                  Case Study 6 ndash Presentation

                                                                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                  Case Study 6 ndash Lab Results

                                                                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                  TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                  PT 63 sec gt control 113 ndash 146 sec

                                                                                                  INR 658 1 ndash 125

                                                                                                  APTT 80 sec gt control 25 ndash 34 sec

                                                                                                  D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                  Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                  Albumin 28 gdL NR

                                                                                                  Hb 58 gdL NR

                                                                                                  LDH 1196 UL NR

                                                                                                  SGPT 144 IU NR

                                                                                                  SGOT 88 IU NR

                                                                                                  Bilirubin 32 mgdL NR

                                                                                                  DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                  day postop

                                                                                                  Case Study 6 ndash Diagnosis and Treatment

                                                                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                  HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                  Case Study 6 ndash Discussion

                                                                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                  44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                  Case Study 7 ndash Presentation

                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                  On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                  Case Study 7 ndash Presentation

                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                  Case Study 7 ndash Lab Results vs Time

                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                  Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                  Case Study 7 ndash Diagnosis and Treatment

                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                  On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                  Case Study 7 ndash Diagnosis and Treatment

                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                  DIC Take Home Messages

                                                                                                  Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                  Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                  DIC

                                                                                                  Thank you Questions

                                                                                                  • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                  • Learning Objectives
                                                                                                  • Slide Number 3
                                                                                                  • Slide Number 4
                                                                                                  • Slide Number 5
                                                                                                  • Slide Number 6
                                                                                                  • Slide Number 7
                                                                                                  • Slide Number 8
                                                                                                  • Wound Sealing
                                                                                                  • The Three Steps of Hemostasis
                                                                                                  • Vessel Wall
                                                                                                  • Slide Number 12
                                                                                                  • Slide Number 13
                                                                                                  • Platelet Structure UnactivatedActivated
                                                                                                  • Primary Hemostasis
                                                                                                  • Primary Hemostasis Assays
                                                                                                  • Slide Number 17
                                                                                                  • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                  • Slide Number 19
                                                                                                  • Coagulation factors
                                                                                                  • Coagulation Assay Mechanisms
                                                                                                  • Slide Number 22
                                                                                                  • Fibrin Formation
                                                                                                  • Slide Number 24
                                                                                                  • Fibrinolysis Overview
                                                                                                  • Fibrinolysis Overview
                                                                                                  • Slide Number 27
                                                                                                  • Fibrinolysis Releases D-dimers
                                                                                                  • Basic Pathophysiology of DIC
                                                                                                  • Disseminated Intravascular Coagulation (DIC)
                                                                                                  • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                  • Clinical Conditions Associated With DIC
                                                                                                  • Frequency of DIC in Selected Disease States
                                                                                                  • Underlying Diseases in DIC Patients
                                                                                                  • Slide Number 36
                                                                                                  • Slide Number 37
                                                                                                  • Slide Number 38
                                                                                                  • Slide Number 39
                                                                                                  • Pathophysiology of DIC
                                                                                                  • Pathogenesis of DIC in Sepsis
                                                                                                  • Host Response in Severe Sepsis
                                                                                                  • Organ Failure in Severe Sepsis
                                                                                                  • Mechanism of DIC in Organ Failure
                                                                                                  • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                  • Slide Number 47
                                                                                                  • Diverse and Opposing Effects of Thrombin
                                                                                                  • Coagulation and Fibrinolysis in DIC
                                                                                                  • Mechanism of DIC
                                                                                                  • Pathophysiology of DIC
                                                                                                  • Pathophysiology of DIC - Mechanism
                                                                                                  • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                  • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                  • Pathophysiology of Overt DIC
                                                                                                  • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                  • Slide Number 57
                                                                                                  • Slide Number 58
                                                                                                  • Slide Number 59
                                                                                                  • Slide Number 60
                                                                                                  • Slide Number 61
                                                                                                  • BREAK
                                                                                                  • Diagnostic and Management Approach for DIC
                                                                                                  • Diagnosis of DIC
                                                                                                  • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                  • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                  • Slide Number 67
                                                                                                  • Slide Number 68
                                                                                                  • British Journal of Haematology Overt DIC Score
                                                                                                  • Slide Number 70
                                                                                                  • Slide Number 71
                                                                                                  • Slide Number 72
                                                                                                  • Slide Number 73
                                                                                                  • DIC Management Goals
                                                                                                  • DIC Management and Treatment
                                                                                                  • DIC Management Strategies
                                                                                                  • Anticoagulant Factor Concentrate Treatment
                                                                                                  • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                  • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                  • D-dimer FDPs and DIC
                                                                                                  • D-Dimer and FDPs in DIC
                                                                                                  • Follow Up of DIC State of Disease
                                                                                                  • FMD-Dimer in DIC Major Differences
                                                                                                  • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                  • Slide Number 85
                                                                                                  • Slide Number 86
                                                                                                  • Comparing an Automated FM vs Manual FSP Test
                                                                                                  • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                  • Slide Number 94
                                                                                                  • Slide Number 95
                                                                                                  • Slide Number 96
                                                                                                  • Slide Number 97
                                                                                                  • Slide Number 98
                                                                                                  • Slide Number 99
                                                                                                  • DIC Case Studies
                                                                                                  • Case Study 1 - Presentation
                                                                                                  • Case Study 1 ndash Lab Results
                                                                                                  • Case Study 1 ndash Microscopy
                                                                                                  • Case Study 1 ndash Diagnosis and Therapy
                                                                                                  • Slide Number 105
                                                                                                  • Slide Number 106
                                                                                                  • Slide Number 107
                                                                                                  • Slide Number 108
                                                                                                  • Slide Number 109
                                                                                                  • Slide Number 110
                                                                                                  • Slide Number 111
                                                                                                  • Slide Number 112
                                                                                                  • Slide Number 113
                                                                                                  • Slide Number 114
                                                                                                  • Slide Number 115
                                                                                                  • Slide Number 116
                                                                                                  • Slide Number 117
                                                                                                  • Slide Number 118
                                                                                                  • Slide Number 119
                                                                                                  • Slide Number 120
                                                                                                  • Slide Number 121
                                                                                                  • Slide Number 122
                                                                                                  • Slide Number 123
                                                                                                  • Slide Number 124
                                                                                                  • Slide Number 125
                                                                                                  • DIC Take Home Messages
                                                                                                  • Slide Number 127
                                                                                                  • Slide Number 128

                                                                                                    Mechanism of DIC

                                                                                                    THROMBOSIS

                                                                                                    Fibrin

                                                                                                    Blood activationEndothelial lysisTF expression

                                                                                                    BLEEDING

                                                                                                    FDPs

                                                                                                    D-Dimer

                                                                                                    Plasmin

                                                                                                    Pathophysiology of DIC

                                                                                                    1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

                                                                                                    thromboplastin influx of activated cells (monocytes macrophages)

                                                                                                    Results in an intravascular deposition of fibrin

                                                                                                    Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

                                                                                                    Second step Consumption and depletion of coagulation factors inhibitors (Protein C

                                                                                                    Protein S AT) and platelets Local fibrinolytic response

                                                                                                    bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

                                                                                                    FDP and D-Dimer

                                                                                                    Bleeding

                                                                                                    Pathophysiology of DIC - Mechanism

                                                                                                    Systemic activation of coagulation

                                                                                                    Intravasculardepositionof fibrin

                                                                                                    Thrombosis of small and midsize vessels

                                                                                                    and organ failure

                                                                                                    Depletion of platelets and

                                                                                                    coagulation factors

                                                                                                    Bleeding

                                                                                                    Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                                                                                    Pathophysiology of DIC ndash 2 Types of Clinical pictures

                                                                                                    Chronic = non - overt DICMay be unrecognized clinically

                                                                                                    Acute = overt DIClife threatening bleedingor multiple organ failure

                                                                                                    Sub-Acute and Non-Overt DIC Clinical Findings

                                                                                                    Compensated non-overt DIC Steady low level or intermittent activation

                                                                                                    bull Compensated by increased production of coagulation components and platelets

                                                                                                    Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                                                                                                    Risk of decompensation leading to overt DIC

                                                                                                    Pathophysiology of Overt DIC

                                                                                                    Massive activation of coagulation and fibrinolysis

                                                                                                    Does not allow for compensatory efforts

                                                                                                    Rapid depletion of coagulation factors inhibitors and platelets

                                                                                                    Thrombosis multiple organ failures

                                                                                                    Bleeding complications and shock

                                                                                                    Physiopathology of DIC ndash Overt DIC Findings

                                                                                                    Thrombin generation

                                                                                                    Thrombosis

                                                                                                    Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                                                                                                    Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                                                                                                    Plasmin generationHemorrhage

                                                                                                    bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                                                                                                    bull Tachycardia hypotension edema

                                                                                                    Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                    Pathogenesis Pathways in DIC

                                                                                                    Cytokines

                                                                                                    TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                                                                                                    fibrin inadequateformation fibrin removal

                                                                                                    Fibrin deposition

                                                                                                    Inflammation

                                                                                                    Coagulation

                                                                                                    Stago Celebrates Lab Week 2017

                                                                                                    NA

                                                                                                    Stago 247 Educational Webinar Sites

                                                                                                    wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                                                                                                    wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                                                                                                    Stago Educational Apps

                                                                                                    HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                                                                                                    iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                                                                                                    BREAK

                                                                                                    Diagnostic and Management Approach for DIC

                                                                                                    Diagnosis of DIC

                                                                                                    Clinical diagnosis is obvious in cases of overt DIC

                                                                                                    Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                                                                                    Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                                                                                    Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                                                                                    Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                                                                                    Important to recognize simultaneous formation of thrombin and plasmin

                                                                                                    Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                                    Lab Diagnosis of DIC ndash Screening Tests

                                                                                                    Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                                    Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                                                                                    fibrinogen level) repeat testing assesses progression

                                                                                                    Screening tests not clinically specific or sensitive for DIC

                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                    Laboratory Changes in Overt DIC

                                                                                                    DIC Diagnostic Practices Over Time

                                                                                                    Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                    British Journal of Haematology Overt DIC Score

                                                                                                    Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                    ISTH Step by Step DIC Algorithm

                                                                                                    Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                                                                    US Based Validation of ISTH DIC Score

                                                                                                    When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                    Differential Diagnosis in DIC

                                                                                                    aHUS atypical hemolytic uremic syndrome

                                                                                                    HUS hemolytic uremic syndrome

                                                                                                    HIT heparin-induced thrombocytopenia

                                                                                                    ITP immune thrombocytopenic purpura

                                                                                                    TTP thrombotic thrombocytopenic purpura

                                                                                                    DIC and MAHA

                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                    lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                                                                    When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                                                                    DIC Management Goals

                                                                                                    Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                    Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                                                                    DIC Management and Treatment

                                                                                                    Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                    Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                                                                    requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                                                                    Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                                                                    DIC Management Strategies

                                                                                                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                    Anticoagulant Factor Concentrate Treatment

                                                                                                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                    Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                                                    Anticoagulant Factor Concentrate Treatment Trials

                                                                                                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                    Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                                                    Markers of Thrombin amp Plasmin Generation in DIC

                                                                                                    D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                                                    Cut-off value

                                                                                                    Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                                                    degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                                                    D-dimer FDPs and DIC

                                                                                                    D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                                                    Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                                                    Follow Up of DIC State of Disease

                                                                                                    Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                                                    Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                                                    FMD-Dimer in DIC Major Differences

                                                                                                    onset of thrombosis

                                                                                                    days

                                                                                                    Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                                                    FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                                                    D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                                                    of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                                                    0

                                                                                                    20

                                                                                                    40

                                                                                                    60

                                                                                                    80

                                                                                                    100

                                                                                                    94 85 90N = 62

                                                                                                    Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                                                    Positivity of Test Results ISTH Score and Disease State

                                                                                                    Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                    Red bar positive for 2 points of DIC score

                                                                                                    Pink bar positive for 1-2 points of DIC score

                                                                                                    HT hematopoietic tumor

                                                                                                    IF infection

                                                                                                    SC solid cancer

                                                                                                    Markers in Patients with or without DIC

                                                                                                    Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                    HT hematopoietic tumorIF infectionSC solid cancer

                                                                                                    Comparing an Automated FM vs Manual FSP Test

                                                                                                    Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                                    Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                                    Automated (Mitsubishi) vs Automated (Stago)

                                                                                                    In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                                    Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                    In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                    In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                    In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                                    Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                    No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                    Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                                    Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                    Non Overt DIC Overt DIC

                                                                                                    AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                    Trends in Markers of DIC for Different Patients

                                                                                                    Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                    Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                    Trends in Markers of DIC for Different Patients

                                                                                                    Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                    FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                    28 day outcome survival

                                                                                                    28 day outcome death

                                                                                                    Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                    Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                    Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                    Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                    Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                    Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                    DIC Case Studies

                                                                                                    Case Study 1 - Presentation

                                                                                                    18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                    Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                    WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                    RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                    Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                    Hematocrit 195 401 ndash 510

                                                                                                    MCV 95 fL 790 ndash 922 fL

                                                                                                    MPV 12 fL 94 ndash 124 fL

                                                                                                    Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                    Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                    Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                    PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                    APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                    Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                    D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                    Case Study 1 ndash Microscopy

                                                                                                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                    Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                    Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                    DIC due to TF release by APL blasts

                                                                                                    Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                    Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                    20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                    Case Study 2 ndash Presentation

                                                                                                    TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                    PT 30 sec 113 ndash 146 sec

                                                                                                    APTT 75 sec 25 ndash 34 sec

                                                                                                    D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                    Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                    pH 728 738 to 742

                                                                                                    PaO2 570 mmHg 80-100 mmHg

                                                                                                    WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                    ALT 111 IUL 0ndash34 IUL

                                                                                                    AST 61 IUL 0ndash34 IUL

                                                                                                    BUN 303 mgdL 08-13 mgdL

                                                                                                    Case Study 2 ndash Lab Results

                                                                                                    Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                    Case Study 2 ndash Diagnosis

                                                                                                    60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                    Case Study 3 ndash Presentation

                                                                                                    TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                    PT 228 sec 113 ndash 146 sec

                                                                                                    APTT 45 sec 25 ndash 34 sec

                                                                                                    D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                    Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                    FV Normal 70-120

                                                                                                    FVII Normal 55-170

                                                                                                    FVIII Normal 60-150

                                                                                                    Protein C Normal 70-130

                                                                                                    Hb 134 gdL 14-16 gdL

                                                                                                    WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                    ALT 32 IUL 0ndash34 IUL

                                                                                                    AST 28 IUL 0ndash34 IUL

                                                                                                    BUN 09 mgdL 08-13 mgdL

                                                                                                    Case Study 3 ndash Lab Results

                                                                                                    Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                    Case Study 3 ndash Diagnosis and Therapy

                                                                                                    Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                    Case Study 4 ndash Presentation

                                                                                                    TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                    PT 28 sec 113 ndash 146 sec

                                                                                                    APTT 71 sec 25 ndash 34 sec

                                                                                                    D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                    Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                    FV Normal 70-120

                                                                                                    FVII Normal 55-170

                                                                                                    FVIII Normal 60-150

                                                                                                    Protein C Normal 70-130

                                                                                                    Hb 158 gdL 14-16 gdL

                                                                                                    WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                    ALT 60 IUL 0ndash34 IUL

                                                                                                    AST 47 IUL 0ndash34 IUL

                                                                                                    BUN 38 mgdL 08-13 mgdL

                                                                                                    Case Study 4 ndash Lab Results

                                                                                                    Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                    Case Study 4 ndash Diagnosis

                                                                                                    55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                    Case Study 5 ndash Presentation

                                                                                                    Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                    Case Study 5 ndash Lab Results and Time Course

                                                                                                    Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                    TEST RESULT REFERENCE RANGE

                                                                                                    Platelet count 33 x 109L 150-450 x 109L

                                                                                                    PT 215 sec 103 ndash 128 sec

                                                                                                    APTT 44 sec 26 ndash 36 sec

                                                                                                    D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                    Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                    FII FV FVIII Low Not reported (NR)

                                                                                                    FVII FIX FX vWF Normal NR

                                                                                                    Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                    DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                    dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                    (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                    (D) Illustration demonstrating repair

                                                                                                    Case Study 5 ndash Diagnosis and Treatment

                                                                                                    Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                    29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                    Case Study 6 ndash Presentation

                                                                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                    Case Study 6 ndash Lab Results

                                                                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                    TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                    PT 63 sec gt control 113 ndash 146 sec

                                                                                                    INR 658 1 ndash 125

                                                                                                    APTT 80 sec gt control 25 ndash 34 sec

                                                                                                    D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                    Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                    Albumin 28 gdL NR

                                                                                                    Hb 58 gdL NR

                                                                                                    LDH 1196 UL NR

                                                                                                    SGPT 144 IU NR

                                                                                                    SGOT 88 IU NR

                                                                                                    Bilirubin 32 mgdL NR

                                                                                                    DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                    day postop

                                                                                                    Case Study 6 ndash Diagnosis and Treatment

                                                                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                    HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                    Case Study 6 ndash Discussion

                                                                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                    44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                    Case Study 7 ndash Presentation

                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                    On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                    Case Study 7 ndash Presentation

                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                    Case Study 7 ndash Lab Results vs Time

                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                    Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                    Case Study 7 ndash Diagnosis and Treatment

                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                    On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                    Case Study 7 ndash Diagnosis and Treatment

                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                    DIC Take Home Messages

                                                                                                    Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                    Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                    DIC

                                                                                                    Thank you Questions

                                                                                                    • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                    • Learning Objectives
                                                                                                    • Slide Number 3
                                                                                                    • Slide Number 4
                                                                                                    • Slide Number 5
                                                                                                    • Slide Number 6
                                                                                                    • Slide Number 7
                                                                                                    • Slide Number 8
                                                                                                    • Wound Sealing
                                                                                                    • The Three Steps of Hemostasis
                                                                                                    • Vessel Wall
                                                                                                    • Slide Number 12
                                                                                                    • Slide Number 13
                                                                                                    • Platelet Structure UnactivatedActivated
                                                                                                    • Primary Hemostasis
                                                                                                    • Primary Hemostasis Assays
                                                                                                    • Slide Number 17
                                                                                                    • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                    • Slide Number 19
                                                                                                    • Coagulation factors
                                                                                                    • Coagulation Assay Mechanisms
                                                                                                    • Slide Number 22
                                                                                                    • Fibrin Formation
                                                                                                    • Slide Number 24
                                                                                                    • Fibrinolysis Overview
                                                                                                    • Fibrinolysis Overview
                                                                                                    • Slide Number 27
                                                                                                    • Fibrinolysis Releases D-dimers
                                                                                                    • Basic Pathophysiology of DIC
                                                                                                    • Disseminated Intravascular Coagulation (DIC)
                                                                                                    • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                    • Clinical Conditions Associated With DIC
                                                                                                    • Frequency of DIC in Selected Disease States
                                                                                                    • Underlying Diseases in DIC Patients
                                                                                                    • Slide Number 36
                                                                                                    • Slide Number 37
                                                                                                    • Slide Number 38
                                                                                                    • Slide Number 39
                                                                                                    • Pathophysiology of DIC
                                                                                                    • Pathogenesis of DIC in Sepsis
                                                                                                    • Host Response in Severe Sepsis
                                                                                                    • Organ Failure in Severe Sepsis
                                                                                                    • Mechanism of DIC in Organ Failure
                                                                                                    • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                    • Slide Number 47
                                                                                                    • Diverse and Opposing Effects of Thrombin
                                                                                                    • Coagulation and Fibrinolysis in DIC
                                                                                                    • Mechanism of DIC
                                                                                                    • Pathophysiology of DIC
                                                                                                    • Pathophysiology of DIC - Mechanism
                                                                                                    • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                    • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                    • Pathophysiology of Overt DIC
                                                                                                    • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                    • Slide Number 57
                                                                                                    • Slide Number 58
                                                                                                    • Slide Number 59
                                                                                                    • Slide Number 60
                                                                                                    • Slide Number 61
                                                                                                    • BREAK
                                                                                                    • Diagnostic and Management Approach for DIC
                                                                                                    • Diagnosis of DIC
                                                                                                    • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                    • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                    • Slide Number 67
                                                                                                    • Slide Number 68
                                                                                                    • British Journal of Haematology Overt DIC Score
                                                                                                    • Slide Number 70
                                                                                                    • Slide Number 71
                                                                                                    • Slide Number 72
                                                                                                    • Slide Number 73
                                                                                                    • DIC Management Goals
                                                                                                    • DIC Management and Treatment
                                                                                                    • DIC Management Strategies
                                                                                                    • Anticoagulant Factor Concentrate Treatment
                                                                                                    • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                    • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                    • D-dimer FDPs and DIC
                                                                                                    • D-Dimer and FDPs in DIC
                                                                                                    • Follow Up of DIC State of Disease
                                                                                                    • FMD-Dimer in DIC Major Differences
                                                                                                    • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                    • Slide Number 85
                                                                                                    • Slide Number 86
                                                                                                    • Comparing an Automated FM vs Manual FSP Test
                                                                                                    • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                    • Slide Number 94
                                                                                                    • Slide Number 95
                                                                                                    • Slide Number 96
                                                                                                    • Slide Number 97
                                                                                                    • Slide Number 98
                                                                                                    • Slide Number 99
                                                                                                    • DIC Case Studies
                                                                                                    • Case Study 1 - Presentation
                                                                                                    • Case Study 1 ndash Lab Results
                                                                                                    • Case Study 1 ndash Microscopy
                                                                                                    • Case Study 1 ndash Diagnosis and Therapy
                                                                                                    • Slide Number 105
                                                                                                    • Slide Number 106
                                                                                                    • Slide Number 107
                                                                                                    • Slide Number 108
                                                                                                    • Slide Number 109
                                                                                                    • Slide Number 110
                                                                                                    • Slide Number 111
                                                                                                    • Slide Number 112
                                                                                                    • Slide Number 113
                                                                                                    • Slide Number 114
                                                                                                    • Slide Number 115
                                                                                                    • Slide Number 116
                                                                                                    • Slide Number 117
                                                                                                    • Slide Number 118
                                                                                                    • Slide Number 119
                                                                                                    • Slide Number 120
                                                                                                    • Slide Number 121
                                                                                                    • Slide Number 122
                                                                                                    • Slide Number 123
                                                                                                    • Slide Number 124
                                                                                                    • Slide Number 125
                                                                                                    • DIC Take Home Messages
                                                                                                    • Slide Number 127
                                                                                                    • Slide Number 128

                                                                                                      Pathophysiology of DIC

                                                                                                      1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of

                                                                                                      thromboplastin influx of activated cells (monocytes macrophages)

                                                                                                      Results in an intravascular deposition of fibrin

                                                                                                      Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure

                                                                                                      Second step Consumption and depletion of coagulation factors inhibitors (Protein C

                                                                                                      Protein S AT) and platelets Local fibrinolytic response

                                                                                                      bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of

                                                                                                      FDP and D-Dimer

                                                                                                      Bleeding

                                                                                                      Pathophysiology of DIC - Mechanism

                                                                                                      Systemic activation of coagulation

                                                                                                      Intravasculardepositionof fibrin

                                                                                                      Thrombosis of small and midsize vessels

                                                                                                      and organ failure

                                                                                                      Depletion of platelets and

                                                                                                      coagulation factors

                                                                                                      Bleeding

                                                                                                      Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                                                                                      Pathophysiology of DIC ndash 2 Types of Clinical pictures

                                                                                                      Chronic = non - overt DICMay be unrecognized clinically

                                                                                                      Acute = overt DIClife threatening bleedingor multiple organ failure

                                                                                                      Sub-Acute and Non-Overt DIC Clinical Findings

                                                                                                      Compensated non-overt DIC Steady low level or intermittent activation

                                                                                                      bull Compensated by increased production of coagulation components and platelets

                                                                                                      Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                                                                                                      Risk of decompensation leading to overt DIC

                                                                                                      Pathophysiology of Overt DIC

                                                                                                      Massive activation of coagulation and fibrinolysis

                                                                                                      Does not allow for compensatory efforts

                                                                                                      Rapid depletion of coagulation factors inhibitors and platelets

                                                                                                      Thrombosis multiple organ failures

                                                                                                      Bleeding complications and shock

                                                                                                      Physiopathology of DIC ndash Overt DIC Findings

                                                                                                      Thrombin generation

                                                                                                      Thrombosis

                                                                                                      Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                                                                                                      Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                                                                                                      Plasmin generationHemorrhage

                                                                                                      bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                                                                                                      bull Tachycardia hypotension edema

                                                                                                      Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                      Pathogenesis Pathways in DIC

                                                                                                      Cytokines

                                                                                                      TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                                                                                                      fibrin inadequateformation fibrin removal

                                                                                                      Fibrin deposition

                                                                                                      Inflammation

                                                                                                      Coagulation

                                                                                                      Stago Celebrates Lab Week 2017

                                                                                                      NA

                                                                                                      Stago 247 Educational Webinar Sites

                                                                                                      wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                                                                                                      wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                                                                                                      Stago Educational Apps

                                                                                                      HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                                                                                                      iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                                                                                                      BREAK

                                                                                                      Diagnostic and Management Approach for DIC

                                                                                                      Diagnosis of DIC

                                                                                                      Clinical diagnosis is obvious in cases of overt DIC

                                                                                                      Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                                                                                      Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                                                                                      Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                                                                                      Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                                                                                      Important to recognize simultaneous formation of thrombin and plasmin

                                                                                                      Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                                      Lab Diagnosis of DIC ndash Screening Tests

                                                                                                      Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                                      Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                                                                                      fibrinogen level) repeat testing assesses progression

                                                                                                      Screening tests not clinically specific or sensitive for DIC

                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                      Laboratory Changes in Overt DIC

                                                                                                      DIC Diagnostic Practices Over Time

                                                                                                      Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                      British Journal of Haematology Overt DIC Score

                                                                                                      Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                      ISTH Step by Step DIC Algorithm

                                                                                                      Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                                                                      US Based Validation of ISTH DIC Score

                                                                                                      When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                      Differential Diagnosis in DIC

                                                                                                      aHUS atypical hemolytic uremic syndrome

                                                                                                      HUS hemolytic uremic syndrome

                                                                                                      HIT heparin-induced thrombocytopenia

                                                                                                      ITP immune thrombocytopenic purpura

                                                                                                      TTP thrombotic thrombocytopenic purpura

                                                                                                      DIC and MAHA

                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                      lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                                                                      When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                                                                      DIC Management Goals

                                                                                                      Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                      Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                                                                      DIC Management and Treatment

                                                                                                      Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                      Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                                                                      requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                                                                      Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                                                                      DIC Management Strategies

                                                                                                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                      Anticoagulant Factor Concentrate Treatment

                                                                                                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                      Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                                                      Anticoagulant Factor Concentrate Treatment Trials

                                                                                                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                      Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                                                      Markers of Thrombin amp Plasmin Generation in DIC

                                                                                                      D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                                                      Cut-off value

                                                                                                      Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                                                      degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                                                      D-dimer FDPs and DIC

                                                                                                      D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                                                      Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                                                      Follow Up of DIC State of Disease

                                                                                                      Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                                                      Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                                                      FMD-Dimer in DIC Major Differences

                                                                                                      onset of thrombosis

                                                                                                      days

                                                                                                      Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                                                      FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                                                      D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                                                      of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                                                      0

                                                                                                      20

                                                                                                      40

                                                                                                      60

                                                                                                      80

                                                                                                      100

                                                                                                      94 85 90N = 62

                                                                                                      Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                                                      Positivity of Test Results ISTH Score and Disease State

                                                                                                      Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                      Red bar positive for 2 points of DIC score

                                                                                                      Pink bar positive for 1-2 points of DIC score

                                                                                                      HT hematopoietic tumor

                                                                                                      IF infection

                                                                                                      SC solid cancer

                                                                                                      Markers in Patients with or without DIC

                                                                                                      Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                      HT hematopoietic tumorIF infectionSC solid cancer

                                                                                                      Comparing an Automated FM vs Manual FSP Test

                                                                                                      Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                                      Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                                      Automated (Mitsubishi) vs Automated (Stago)

                                                                                                      In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                                      Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                      In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                      In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                      In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                                      Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                      No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                      Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                                      Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                      Non Overt DIC Overt DIC

                                                                                                      AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                      Trends in Markers of DIC for Different Patients

                                                                                                      Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                      Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                      Trends in Markers of DIC for Different Patients

                                                                                                      Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                      FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                      28 day outcome survival

                                                                                                      28 day outcome death

                                                                                                      Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                      Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                      Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                      Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                      Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                      Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                      DIC Case Studies

                                                                                                      Case Study 1 - Presentation

                                                                                                      18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                      Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                      WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                      RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                      Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                      Hematocrit 195 401 ndash 510

                                                                                                      MCV 95 fL 790 ndash 922 fL

                                                                                                      MPV 12 fL 94 ndash 124 fL

                                                                                                      Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                      Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                      Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                      PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                      APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                      Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                      D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                      Case Study 1 ndash Microscopy

                                                                                                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                      Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                      Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                      DIC due to TF release by APL blasts

                                                                                                      Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                      Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                      20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                      Case Study 2 ndash Presentation

                                                                                                      TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                      PT 30 sec 113 ndash 146 sec

                                                                                                      APTT 75 sec 25 ndash 34 sec

                                                                                                      D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                      Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                      pH 728 738 to 742

                                                                                                      PaO2 570 mmHg 80-100 mmHg

                                                                                                      WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                      ALT 111 IUL 0ndash34 IUL

                                                                                                      AST 61 IUL 0ndash34 IUL

                                                                                                      BUN 303 mgdL 08-13 mgdL

                                                                                                      Case Study 2 ndash Lab Results

                                                                                                      Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                      Case Study 2 ndash Diagnosis

                                                                                                      60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                      Case Study 3 ndash Presentation

                                                                                                      TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                      PT 228 sec 113 ndash 146 sec

                                                                                                      APTT 45 sec 25 ndash 34 sec

                                                                                                      D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                      Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                      FV Normal 70-120

                                                                                                      FVII Normal 55-170

                                                                                                      FVIII Normal 60-150

                                                                                                      Protein C Normal 70-130

                                                                                                      Hb 134 gdL 14-16 gdL

                                                                                                      WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                      ALT 32 IUL 0ndash34 IUL

                                                                                                      AST 28 IUL 0ndash34 IUL

                                                                                                      BUN 09 mgdL 08-13 mgdL

                                                                                                      Case Study 3 ndash Lab Results

                                                                                                      Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                      Case Study 3 ndash Diagnosis and Therapy

                                                                                                      Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                      Case Study 4 ndash Presentation

                                                                                                      TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                      PT 28 sec 113 ndash 146 sec

                                                                                                      APTT 71 sec 25 ndash 34 sec

                                                                                                      D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                      Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                      FV Normal 70-120

                                                                                                      FVII Normal 55-170

                                                                                                      FVIII Normal 60-150

                                                                                                      Protein C Normal 70-130

                                                                                                      Hb 158 gdL 14-16 gdL

                                                                                                      WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                      ALT 60 IUL 0ndash34 IUL

                                                                                                      AST 47 IUL 0ndash34 IUL

                                                                                                      BUN 38 mgdL 08-13 mgdL

                                                                                                      Case Study 4 ndash Lab Results

                                                                                                      Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                      Case Study 4 ndash Diagnosis

                                                                                                      55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                      Case Study 5 ndash Presentation

                                                                                                      Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                      Case Study 5 ndash Lab Results and Time Course

                                                                                                      Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                      TEST RESULT REFERENCE RANGE

                                                                                                      Platelet count 33 x 109L 150-450 x 109L

                                                                                                      PT 215 sec 103 ndash 128 sec

                                                                                                      APTT 44 sec 26 ndash 36 sec

                                                                                                      D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                      Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                      FII FV FVIII Low Not reported (NR)

                                                                                                      FVII FIX FX vWF Normal NR

                                                                                                      Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                      DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                      dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                      (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                      (D) Illustration demonstrating repair

                                                                                                      Case Study 5 ndash Diagnosis and Treatment

                                                                                                      Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                      29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                      Case Study 6 ndash Presentation

                                                                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                      Case Study 6 ndash Lab Results

                                                                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                      TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                      PT 63 sec gt control 113 ndash 146 sec

                                                                                                      INR 658 1 ndash 125

                                                                                                      APTT 80 sec gt control 25 ndash 34 sec

                                                                                                      D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                      Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                      Albumin 28 gdL NR

                                                                                                      Hb 58 gdL NR

                                                                                                      LDH 1196 UL NR

                                                                                                      SGPT 144 IU NR

                                                                                                      SGOT 88 IU NR

                                                                                                      Bilirubin 32 mgdL NR

                                                                                                      DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                      day postop

                                                                                                      Case Study 6 ndash Diagnosis and Treatment

                                                                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                      HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                      Case Study 6 ndash Discussion

                                                                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                      44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                      Case Study 7 ndash Presentation

                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                      On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                      Case Study 7 ndash Presentation

                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                      Case Study 7 ndash Lab Results vs Time

                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                      Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                      Case Study 7 ndash Diagnosis and Treatment

                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                      On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                      Case Study 7 ndash Diagnosis and Treatment

                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                      DIC Take Home Messages

                                                                                                      Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                      Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                      DIC

                                                                                                      Thank you Questions

                                                                                                      • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                      • Learning Objectives
                                                                                                      • Slide Number 3
                                                                                                      • Slide Number 4
                                                                                                      • Slide Number 5
                                                                                                      • Slide Number 6
                                                                                                      • Slide Number 7
                                                                                                      • Slide Number 8
                                                                                                      • Wound Sealing
                                                                                                      • The Three Steps of Hemostasis
                                                                                                      • Vessel Wall
                                                                                                      • Slide Number 12
                                                                                                      • Slide Number 13
                                                                                                      • Platelet Structure UnactivatedActivated
                                                                                                      • Primary Hemostasis
                                                                                                      • Primary Hemostasis Assays
                                                                                                      • Slide Number 17
                                                                                                      • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                      • Slide Number 19
                                                                                                      • Coagulation factors
                                                                                                      • Coagulation Assay Mechanisms
                                                                                                      • Slide Number 22
                                                                                                      • Fibrin Formation
                                                                                                      • Slide Number 24
                                                                                                      • Fibrinolysis Overview
                                                                                                      • Fibrinolysis Overview
                                                                                                      • Slide Number 27
                                                                                                      • Fibrinolysis Releases D-dimers
                                                                                                      • Basic Pathophysiology of DIC
                                                                                                      • Disseminated Intravascular Coagulation (DIC)
                                                                                                      • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                      • Clinical Conditions Associated With DIC
                                                                                                      • Frequency of DIC in Selected Disease States
                                                                                                      • Underlying Diseases in DIC Patients
                                                                                                      • Slide Number 36
                                                                                                      • Slide Number 37
                                                                                                      • Slide Number 38
                                                                                                      • Slide Number 39
                                                                                                      • Pathophysiology of DIC
                                                                                                      • Pathogenesis of DIC in Sepsis
                                                                                                      • Host Response in Severe Sepsis
                                                                                                      • Organ Failure in Severe Sepsis
                                                                                                      • Mechanism of DIC in Organ Failure
                                                                                                      • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                      • Slide Number 47
                                                                                                      • Diverse and Opposing Effects of Thrombin
                                                                                                      • Coagulation and Fibrinolysis in DIC
                                                                                                      • Mechanism of DIC
                                                                                                      • Pathophysiology of DIC
                                                                                                      • Pathophysiology of DIC - Mechanism
                                                                                                      • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                      • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                      • Pathophysiology of Overt DIC
                                                                                                      • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                      • Slide Number 57
                                                                                                      • Slide Number 58
                                                                                                      • Slide Number 59
                                                                                                      • Slide Number 60
                                                                                                      • Slide Number 61
                                                                                                      • BREAK
                                                                                                      • Diagnostic and Management Approach for DIC
                                                                                                      • Diagnosis of DIC
                                                                                                      • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                      • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                      • Slide Number 67
                                                                                                      • Slide Number 68
                                                                                                      • British Journal of Haematology Overt DIC Score
                                                                                                      • Slide Number 70
                                                                                                      • Slide Number 71
                                                                                                      • Slide Number 72
                                                                                                      • Slide Number 73
                                                                                                      • DIC Management Goals
                                                                                                      • DIC Management and Treatment
                                                                                                      • DIC Management Strategies
                                                                                                      • Anticoagulant Factor Concentrate Treatment
                                                                                                      • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                      • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                      • D-dimer FDPs and DIC
                                                                                                      • D-Dimer and FDPs in DIC
                                                                                                      • Follow Up of DIC State of Disease
                                                                                                      • FMD-Dimer in DIC Major Differences
                                                                                                      • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                      • Slide Number 85
                                                                                                      • Slide Number 86
                                                                                                      • Comparing an Automated FM vs Manual FSP Test
                                                                                                      • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                      • Slide Number 94
                                                                                                      • Slide Number 95
                                                                                                      • Slide Number 96
                                                                                                      • Slide Number 97
                                                                                                      • Slide Number 98
                                                                                                      • Slide Number 99
                                                                                                      • DIC Case Studies
                                                                                                      • Case Study 1 - Presentation
                                                                                                      • Case Study 1 ndash Lab Results
                                                                                                      • Case Study 1 ndash Microscopy
                                                                                                      • Case Study 1 ndash Diagnosis and Therapy
                                                                                                      • Slide Number 105
                                                                                                      • Slide Number 106
                                                                                                      • Slide Number 107
                                                                                                      • Slide Number 108
                                                                                                      • Slide Number 109
                                                                                                      • Slide Number 110
                                                                                                      • Slide Number 111
                                                                                                      • Slide Number 112
                                                                                                      • Slide Number 113
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                                                                                                      • Slide Number 115
                                                                                                      • Slide Number 116
                                                                                                      • Slide Number 117
                                                                                                      • Slide Number 118
                                                                                                      • Slide Number 119
                                                                                                      • Slide Number 120
                                                                                                      • Slide Number 121
                                                                                                      • Slide Number 122
                                                                                                      • Slide Number 123
                                                                                                      • Slide Number 124
                                                                                                      • Slide Number 125
                                                                                                      • DIC Take Home Messages
                                                                                                      • Slide Number 127
                                                                                                      • Slide Number 128

                                                                                                        Pathophysiology of DIC - Mechanism

                                                                                                        Systemic activation of coagulation

                                                                                                        Intravasculardepositionof fibrin

                                                                                                        Thrombosis of small and midsize vessels

                                                                                                        and organ failure

                                                                                                        Depletion of platelets and

                                                                                                        coagulation factors

                                                                                                        Bleeding

                                                                                                        Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92

                                                                                                        Pathophysiology of DIC ndash 2 Types of Clinical pictures

                                                                                                        Chronic = non - overt DICMay be unrecognized clinically

                                                                                                        Acute = overt DIClife threatening bleedingor multiple organ failure

                                                                                                        Sub-Acute and Non-Overt DIC Clinical Findings

                                                                                                        Compensated non-overt DIC Steady low level or intermittent activation

                                                                                                        bull Compensated by increased production of coagulation components and platelets

                                                                                                        Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                                                                                                        Risk of decompensation leading to overt DIC

                                                                                                        Pathophysiology of Overt DIC

                                                                                                        Massive activation of coagulation and fibrinolysis

                                                                                                        Does not allow for compensatory efforts

                                                                                                        Rapid depletion of coagulation factors inhibitors and platelets

                                                                                                        Thrombosis multiple organ failures

                                                                                                        Bleeding complications and shock

                                                                                                        Physiopathology of DIC ndash Overt DIC Findings

                                                                                                        Thrombin generation

                                                                                                        Thrombosis

                                                                                                        Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                                                                                                        Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                                                                                                        Plasmin generationHemorrhage

                                                                                                        bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                                                                                                        bull Tachycardia hypotension edema

                                                                                                        Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                        Pathogenesis Pathways in DIC

                                                                                                        Cytokines

                                                                                                        TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                                                                                                        fibrin inadequateformation fibrin removal

                                                                                                        Fibrin deposition

                                                                                                        Inflammation

                                                                                                        Coagulation

                                                                                                        Stago Celebrates Lab Week 2017

                                                                                                        NA

                                                                                                        Stago 247 Educational Webinar Sites

                                                                                                        wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                                                                                                        wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                                                                                                        Stago Educational Apps

                                                                                                        HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                                                                                                        iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                                                                                                        BREAK

                                                                                                        Diagnostic and Management Approach for DIC

                                                                                                        Diagnosis of DIC

                                                                                                        Clinical diagnosis is obvious in cases of overt DIC

                                                                                                        Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                                                                                        Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                                                                                        Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                                                                                        Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                                                                                        Important to recognize simultaneous formation of thrombin and plasmin

                                                                                                        Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                                        Lab Diagnosis of DIC ndash Screening Tests

                                                                                                        Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                                        Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                                                                                        fibrinogen level) repeat testing assesses progression

                                                                                                        Screening tests not clinically specific or sensitive for DIC

                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                        Laboratory Changes in Overt DIC

                                                                                                        DIC Diagnostic Practices Over Time

                                                                                                        Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                        British Journal of Haematology Overt DIC Score

                                                                                                        Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                        ISTH Step by Step DIC Algorithm

                                                                                                        Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                                                                        US Based Validation of ISTH DIC Score

                                                                                                        When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                        Differential Diagnosis in DIC

                                                                                                        aHUS atypical hemolytic uremic syndrome

                                                                                                        HUS hemolytic uremic syndrome

                                                                                                        HIT heparin-induced thrombocytopenia

                                                                                                        ITP immune thrombocytopenic purpura

                                                                                                        TTP thrombotic thrombocytopenic purpura

                                                                                                        DIC and MAHA

                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                        lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                                                                        When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                                                                        DIC Management Goals

                                                                                                        Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                        Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                                                                        DIC Management and Treatment

                                                                                                        Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                        Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                                                                        requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                                                                        Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                                                                        DIC Management Strategies

                                                                                                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                        Anticoagulant Factor Concentrate Treatment

                                                                                                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                        Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                                                        Anticoagulant Factor Concentrate Treatment Trials

                                                                                                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                        Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                                                        Markers of Thrombin amp Plasmin Generation in DIC

                                                                                                        D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                                                        Cut-off value

                                                                                                        Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                                                        degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                                                        D-dimer FDPs and DIC

                                                                                                        D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                                                        Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                                                        Follow Up of DIC State of Disease

                                                                                                        Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                                                        Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                                                        FMD-Dimer in DIC Major Differences

                                                                                                        onset of thrombosis

                                                                                                        days

                                                                                                        Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                                                        FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                                                        D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                                                        of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                                                        0

                                                                                                        20

                                                                                                        40

                                                                                                        60

                                                                                                        80

                                                                                                        100

                                                                                                        94 85 90N = 62

                                                                                                        Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                                                        Positivity of Test Results ISTH Score and Disease State

                                                                                                        Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                        Red bar positive for 2 points of DIC score

                                                                                                        Pink bar positive for 1-2 points of DIC score

                                                                                                        HT hematopoietic tumor

                                                                                                        IF infection

                                                                                                        SC solid cancer

                                                                                                        Markers in Patients with or without DIC

                                                                                                        Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                        HT hematopoietic tumorIF infectionSC solid cancer

                                                                                                        Comparing an Automated FM vs Manual FSP Test

                                                                                                        Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                                        Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                                        Automated (Mitsubishi) vs Automated (Stago)

                                                                                                        In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                                        Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                        In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                        In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                        In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                                        Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                        No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                        Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                                        Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                        Non Overt DIC Overt DIC

                                                                                                        AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                        Trends in Markers of DIC for Different Patients

                                                                                                        Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                        Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                        Trends in Markers of DIC for Different Patients

                                                                                                        Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                        FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                        28 day outcome survival

                                                                                                        28 day outcome death

                                                                                                        Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                        Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                        Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                        Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                        Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                        Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                        DIC Case Studies

                                                                                                        Case Study 1 - Presentation

                                                                                                        18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                        Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                        WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                        RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                        Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                        Hematocrit 195 401 ndash 510

                                                                                                        MCV 95 fL 790 ndash 922 fL

                                                                                                        MPV 12 fL 94 ndash 124 fL

                                                                                                        Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                        Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                        Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                        PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                        APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                        Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                        D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                        Case Study 1 ndash Microscopy

                                                                                                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                        Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                        Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                        DIC due to TF release by APL blasts

                                                                                                        Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                        Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                        20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                        Case Study 2 ndash Presentation

                                                                                                        TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                        PT 30 sec 113 ndash 146 sec

                                                                                                        APTT 75 sec 25 ndash 34 sec

                                                                                                        D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                        Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                        pH 728 738 to 742

                                                                                                        PaO2 570 mmHg 80-100 mmHg

                                                                                                        WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                        ALT 111 IUL 0ndash34 IUL

                                                                                                        AST 61 IUL 0ndash34 IUL

                                                                                                        BUN 303 mgdL 08-13 mgdL

                                                                                                        Case Study 2 ndash Lab Results

                                                                                                        Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                        Case Study 2 ndash Diagnosis

                                                                                                        60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                        Case Study 3 ndash Presentation

                                                                                                        TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                        PT 228 sec 113 ndash 146 sec

                                                                                                        APTT 45 sec 25 ndash 34 sec

                                                                                                        D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                        Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                        FV Normal 70-120

                                                                                                        FVII Normal 55-170

                                                                                                        FVIII Normal 60-150

                                                                                                        Protein C Normal 70-130

                                                                                                        Hb 134 gdL 14-16 gdL

                                                                                                        WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                        ALT 32 IUL 0ndash34 IUL

                                                                                                        AST 28 IUL 0ndash34 IUL

                                                                                                        BUN 09 mgdL 08-13 mgdL

                                                                                                        Case Study 3 ndash Lab Results

                                                                                                        Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                        Case Study 3 ndash Diagnosis and Therapy

                                                                                                        Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                        Case Study 4 ndash Presentation

                                                                                                        TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                        PT 28 sec 113 ndash 146 sec

                                                                                                        APTT 71 sec 25 ndash 34 sec

                                                                                                        D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                        Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                        FV Normal 70-120

                                                                                                        FVII Normal 55-170

                                                                                                        FVIII Normal 60-150

                                                                                                        Protein C Normal 70-130

                                                                                                        Hb 158 gdL 14-16 gdL

                                                                                                        WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                        ALT 60 IUL 0ndash34 IUL

                                                                                                        AST 47 IUL 0ndash34 IUL

                                                                                                        BUN 38 mgdL 08-13 mgdL

                                                                                                        Case Study 4 ndash Lab Results

                                                                                                        Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                        Case Study 4 ndash Diagnosis

                                                                                                        55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                        Case Study 5 ndash Presentation

                                                                                                        Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                        Case Study 5 ndash Lab Results and Time Course

                                                                                                        Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                        TEST RESULT REFERENCE RANGE

                                                                                                        Platelet count 33 x 109L 150-450 x 109L

                                                                                                        PT 215 sec 103 ndash 128 sec

                                                                                                        APTT 44 sec 26 ndash 36 sec

                                                                                                        D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                        Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                        FII FV FVIII Low Not reported (NR)

                                                                                                        FVII FIX FX vWF Normal NR

                                                                                                        Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                        DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                        dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                        (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                        (D) Illustration demonstrating repair

                                                                                                        Case Study 5 ndash Diagnosis and Treatment

                                                                                                        Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                        29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                        Case Study 6 ndash Presentation

                                                                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                        Case Study 6 ndash Lab Results

                                                                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                        TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                        PT 63 sec gt control 113 ndash 146 sec

                                                                                                        INR 658 1 ndash 125

                                                                                                        APTT 80 sec gt control 25 ndash 34 sec

                                                                                                        D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                        Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                        Albumin 28 gdL NR

                                                                                                        Hb 58 gdL NR

                                                                                                        LDH 1196 UL NR

                                                                                                        SGPT 144 IU NR

                                                                                                        SGOT 88 IU NR

                                                                                                        Bilirubin 32 mgdL NR

                                                                                                        DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                        day postop

                                                                                                        Case Study 6 ndash Diagnosis and Treatment

                                                                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                        HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                        Case Study 6 ndash Discussion

                                                                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                        44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                        Case Study 7 ndash Presentation

                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                        On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                        Case Study 7 ndash Presentation

                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                        Case Study 7 ndash Lab Results vs Time

                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                        Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                        Case Study 7 ndash Diagnosis and Treatment

                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                        On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                        Case Study 7 ndash Diagnosis and Treatment

                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                        DIC Take Home Messages

                                                                                                        Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                        Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                        DIC

                                                                                                        Thank you Questions

                                                                                                        • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                        • Learning Objectives
                                                                                                        • Slide Number 3
                                                                                                        • Slide Number 4
                                                                                                        • Slide Number 5
                                                                                                        • Slide Number 6
                                                                                                        • Slide Number 7
                                                                                                        • Slide Number 8
                                                                                                        • Wound Sealing
                                                                                                        • The Three Steps of Hemostasis
                                                                                                        • Vessel Wall
                                                                                                        • Slide Number 12
                                                                                                        • Slide Number 13
                                                                                                        • Platelet Structure UnactivatedActivated
                                                                                                        • Primary Hemostasis
                                                                                                        • Primary Hemostasis Assays
                                                                                                        • Slide Number 17
                                                                                                        • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                        • Slide Number 19
                                                                                                        • Coagulation factors
                                                                                                        • Coagulation Assay Mechanisms
                                                                                                        • Slide Number 22
                                                                                                        • Fibrin Formation
                                                                                                        • Slide Number 24
                                                                                                        • Fibrinolysis Overview
                                                                                                        • Fibrinolysis Overview
                                                                                                        • Slide Number 27
                                                                                                        • Fibrinolysis Releases D-dimers
                                                                                                        • Basic Pathophysiology of DIC
                                                                                                        • Disseminated Intravascular Coagulation (DIC)
                                                                                                        • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                        • Clinical Conditions Associated With DIC
                                                                                                        • Frequency of DIC in Selected Disease States
                                                                                                        • Underlying Diseases in DIC Patients
                                                                                                        • Slide Number 36
                                                                                                        • Slide Number 37
                                                                                                        • Slide Number 38
                                                                                                        • Slide Number 39
                                                                                                        • Pathophysiology of DIC
                                                                                                        • Pathogenesis of DIC in Sepsis
                                                                                                        • Host Response in Severe Sepsis
                                                                                                        • Organ Failure in Severe Sepsis
                                                                                                        • Mechanism of DIC in Organ Failure
                                                                                                        • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                        • Slide Number 47
                                                                                                        • Diverse and Opposing Effects of Thrombin
                                                                                                        • Coagulation and Fibrinolysis in DIC
                                                                                                        • Mechanism of DIC
                                                                                                        • Pathophysiology of DIC
                                                                                                        • Pathophysiology of DIC - Mechanism
                                                                                                        • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                        • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                        • Pathophysiology of Overt DIC
                                                                                                        • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                        • Slide Number 57
                                                                                                        • Slide Number 58
                                                                                                        • Slide Number 59
                                                                                                        • Slide Number 60
                                                                                                        • Slide Number 61
                                                                                                        • BREAK
                                                                                                        • Diagnostic and Management Approach for DIC
                                                                                                        • Diagnosis of DIC
                                                                                                        • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                        • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                        • Slide Number 67
                                                                                                        • Slide Number 68
                                                                                                        • British Journal of Haematology Overt DIC Score
                                                                                                        • Slide Number 70
                                                                                                        • Slide Number 71
                                                                                                        • Slide Number 72
                                                                                                        • Slide Number 73
                                                                                                        • DIC Management Goals
                                                                                                        • DIC Management and Treatment
                                                                                                        • DIC Management Strategies
                                                                                                        • Anticoagulant Factor Concentrate Treatment
                                                                                                        • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                        • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                        • D-dimer FDPs and DIC
                                                                                                        • D-Dimer and FDPs in DIC
                                                                                                        • Follow Up of DIC State of Disease
                                                                                                        • FMD-Dimer in DIC Major Differences
                                                                                                        • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                        • Slide Number 85
                                                                                                        • Slide Number 86
                                                                                                        • Comparing an Automated FM vs Manual FSP Test
                                                                                                        • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                        • Slide Number 94
                                                                                                        • Slide Number 95
                                                                                                        • Slide Number 96
                                                                                                        • Slide Number 97
                                                                                                        • Slide Number 98
                                                                                                        • Slide Number 99
                                                                                                        • DIC Case Studies
                                                                                                        • Case Study 1 - Presentation
                                                                                                        • Case Study 1 ndash Lab Results
                                                                                                        • Case Study 1 ndash Microscopy
                                                                                                        • Case Study 1 ndash Diagnosis and Therapy
                                                                                                        • Slide Number 105
                                                                                                        • Slide Number 106
                                                                                                        • Slide Number 107
                                                                                                        • Slide Number 108
                                                                                                        • Slide Number 109
                                                                                                        • Slide Number 110
                                                                                                        • Slide Number 111
                                                                                                        • Slide Number 112
                                                                                                        • Slide Number 113
                                                                                                        • Slide Number 114
                                                                                                        • Slide Number 115
                                                                                                        • Slide Number 116
                                                                                                        • Slide Number 117
                                                                                                        • Slide Number 118
                                                                                                        • Slide Number 119
                                                                                                        • Slide Number 120
                                                                                                        • Slide Number 121
                                                                                                        • Slide Number 122
                                                                                                        • Slide Number 123
                                                                                                        • Slide Number 124
                                                                                                        • Slide Number 125
                                                                                                        • DIC Take Home Messages
                                                                                                        • Slide Number 127
                                                                                                        • Slide Number 128

                                                                                                          Pathophysiology of DIC ndash 2 Types of Clinical pictures

                                                                                                          Chronic = non - overt DICMay be unrecognized clinically

                                                                                                          Acute = overt DIClife threatening bleedingor multiple organ failure

                                                                                                          Sub-Acute and Non-Overt DIC Clinical Findings

                                                                                                          Compensated non-overt DIC Steady low level or intermittent activation

                                                                                                          bull Compensated by increased production of coagulation components and platelets

                                                                                                          Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                                                                                                          Risk of decompensation leading to overt DIC

                                                                                                          Pathophysiology of Overt DIC

                                                                                                          Massive activation of coagulation and fibrinolysis

                                                                                                          Does not allow for compensatory efforts

                                                                                                          Rapid depletion of coagulation factors inhibitors and platelets

                                                                                                          Thrombosis multiple organ failures

                                                                                                          Bleeding complications and shock

                                                                                                          Physiopathology of DIC ndash Overt DIC Findings

                                                                                                          Thrombin generation

                                                                                                          Thrombosis

                                                                                                          Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                                                                                                          Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                                                                                                          Plasmin generationHemorrhage

                                                                                                          bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                                                                                                          bull Tachycardia hypotension edema

                                                                                                          Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                          Pathogenesis Pathways in DIC

                                                                                                          Cytokines

                                                                                                          TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                                                                                                          fibrin inadequateformation fibrin removal

                                                                                                          Fibrin deposition

                                                                                                          Inflammation

                                                                                                          Coagulation

                                                                                                          Stago Celebrates Lab Week 2017

                                                                                                          NA

                                                                                                          Stago 247 Educational Webinar Sites

                                                                                                          wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                                                                                                          wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                                                                                                          Stago Educational Apps

                                                                                                          HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                                                                                                          iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                                                                                                          BREAK

                                                                                                          Diagnostic and Management Approach for DIC

                                                                                                          Diagnosis of DIC

                                                                                                          Clinical diagnosis is obvious in cases of overt DIC

                                                                                                          Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                                                                                          Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                                                                                          Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                                                                                          Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                                                                                          Important to recognize simultaneous formation of thrombin and plasmin

                                                                                                          Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                                          Lab Diagnosis of DIC ndash Screening Tests

                                                                                                          Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                                          Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                                                                                          fibrinogen level) repeat testing assesses progression

                                                                                                          Screening tests not clinically specific or sensitive for DIC

                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                          Laboratory Changes in Overt DIC

                                                                                                          DIC Diagnostic Practices Over Time

                                                                                                          Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                          British Journal of Haematology Overt DIC Score

                                                                                                          Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                          ISTH Step by Step DIC Algorithm

                                                                                                          Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                                                                          US Based Validation of ISTH DIC Score

                                                                                                          When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                          Differential Diagnosis in DIC

                                                                                                          aHUS atypical hemolytic uremic syndrome

                                                                                                          HUS hemolytic uremic syndrome

                                                                                                          HIT heparin-induced thrombocytopenia

                                                                                                          ITP immune thrombocytopenic purpura

                                                                                                          TTP thrombotic thrombocytopenic purpura

                                                                                                          DIC and MAHA

                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                          lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                                                                          When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                                                                          DIC Management Goals

                                                                                                          Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                          Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                                                                          DIC Management and Treatment

                                                                                                          Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                          Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                                                                          requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                                                                          Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                                                                          DIC Management Strategies

                                                                                                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                          Anticoagulant Factor Concentrate Treatment

                                                                                                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                          Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                                                          Anticoagulant Factor Concentrate Treatment Trials

                                                                                                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                          Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                                                          Markers of Thrombin amp Plasmin Generation in DIC

                                                                                                          D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                                                          Cut-off value

                                                                                                          Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                                                          degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                                                          D-dimer FDPs and DIC

                                                                                                          D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                                                          Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                                                          Follow Up of DIC State of Disease

                                                                                                          Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                                                          Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                                                          FMD-Dimer in DIC Major Differences

                                                                                                          onset of thrombosis

                                                                                                          days

                                                                                                          Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                                                          FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                                                          D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                                                          of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                                                          0

                                                                                                          20

                                                                                                          40

                                                                                                          60

                                                                                                          80

                                                                                                          100

                                                                                                          94 85 90N = 62

                                                                                                          Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                                                          Positivity of Test Results ISTH Score and Disease State

                                                                                                          Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                          Red bar positive for 2 points of DIC score

                                                                                                          Pink bar positive for 1-2 points of DIC score

                                                                                                          HT hematopoietic tumor

                                                                                                          IF infection

                                                                                                          SC solid cancer

                                                                                                          Markers in Patients with or without DIC

                                                                                                          Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                          HT hematopoietic tumorIF infectionSC solid cancer

                                                                                                          Comparing an Automated FM vs Manual FSP Test

                                                                                                          Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                                          Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                                          Automated (Mitsubishi) vs Automated (Stago)

                                                                                                          In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                                          Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                          In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                          In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                          In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                                                          Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                          No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                          Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                                                          Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                          Non Overt DIC Overt DIC

                                                                                                          AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                          Trends in Markers of DIC for Different Patients

                                                                                                          Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                          Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                          Trends in Markers of DIC for Different Patients

                                                                                                          Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                          FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                          28 day outcome survival

                                                                                                          28 day outcome death

                                                                                                          Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                          Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                          Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                          Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                          Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                          Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                          DIC Case Studies

                                                                                                          Case Study 1 - Presentation

                                                                                                          18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                          Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                          WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                          RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                          Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                          Hematocrit 195 401 ndash 510

                                                                                                          MCV 95 fL 790 ndash 922 fL

                                                                                                          MPV 12 fL 94 ndash 124 fL

                                                                                                          Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                          Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                          Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                          PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                          APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                          Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                          D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                          Case Study 1 ndash Microscopy

                                                                                                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                          Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                          Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                          DIC due to TF release by APL blasts

                                                                                                          Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                          Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                          20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                          Case Study 2 ndash Presentation

                                                                                                          TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                          PT 30 sec 113 ndash 146 sec

                                                                                                          APTT 75 sec 25 ndash 34 sec

                                                                                                          D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                          Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                          pH 728 738 to 742

                                                                                                          PaO2 570 mmHg 80-100 mmHg

                                                                                                          WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                          ALT 111 IUL 0ndash34 IUL

                                                                                                          AST 61 IUL 0ndash34 IUL

                                                                                                          BUN 303 mgdL 08-13 mgdL

                                                                                                          Case Study 2 ndash Lab Results

                                                                                                          Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                          Case Study 2 ndash Diagnosis

                                                                                                          60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                          Case Study 3 ndash Presentation

                                                                                                          TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                          PT 228 sec 113 ndash 146 sec

                                                                                                          APTT 45 sec 25 ndash 34 sec

                                                                                                          D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                          Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                          FV Normal 70-120

                                                                                                          FVII Normal 55-170

                                                                                                          FVIII Normal 60-150

                                                                                                          Protein C Normal 70-130

                                                                                                          Hb 134 gdL 14-16 gdL

                                                                                                          WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                          ALT 32 IUL 0ndash34 IUL

                                                                                                          AST 28 IUL 0ndash34 IUL

                                                                                                          BUN 09 mgdL 08-13 mgdL

                                                                                                          Case Study 3 ndash Lab Results

                                                                                                          Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                          Case Study 3 ndash Diagnosis and Therapy

                                                                                                          Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                          Case Study 4 ndash Presentation

                                                                                                          TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                          PT 28 sec 113 ndash 146 sec

                                                                                                          APTT 71 sec 25 ndash 34 sec

                                                                                                          D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                          Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                          FV Normal 70-120

                                                                                                          FVII Normal 55-170

                                                                                                          FVIII Normal 60-150

                                                                                                          Protein C Normal 70-130

                                                                                                          Hb 158 gdL 14-16 gdL

                                                                                                          WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                          ALT 60 IUL 0ndash34 IUL

                                                                                                          AST 47 IUL 0ndash34 IUL

                                                                                                          BUN 38 mgdL 08-13 mgdL

                                                                                                          Case Study 4 ndash Lab Results

                                                                                                          Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                          Case Study 4 ndash Diagnosis

                                                                                                          55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                          Case Study 5 ndash Presentation

                                                                                                          Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                          Case Study 5 ndash Lab Results and Time Course

                                                                                                          Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                          TEST RESULT REFERENCE RANGE

                                                                                                          Platelet count 33 x 109L 150-450 x 109L

                                                                                                          PT 215 sec 103 ndash 128 sec

                                                                                                          APTT 44 sec 26 ndash 36 sec

                                                                                                          D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                          Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                          FII FV FVIII Low Not reported (NR)

                                                                                                          FVII FIX FX vWF Normal NR

                                                                                                          Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                          DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                          dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                          (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                          (D) Illustration demonstrating repair

                                                                                                          Case Study 5 ndash Diagnosis and Treatment

                                                                                                          Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                          29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                          Case Study 6 ndash Presentation

                                                                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                          Case Study 6 ndash Lab Results

                                                                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                          TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                          PT 63 sec gt control 113 ndash 146 sec

                                                                                                          INR 658 1 ndash 125

                                                                                                          APTT 80 sec gt control 25 ndash 34 sec

                                                                                                          D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                          Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                          Albumin 28 gdL NR

                                                                                                          Hb 58 gdL NR

                                                                                                          LDH 1196 UL NR

                                                                                                          SGPT 144 IU NR

                                                                                                          SGOT 88 IU NR

                                                                                                          Bilirubin 32 mgdL NR

                                                                                                          DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                          day postop

                                                                                                          Case Study 6 ndash Diagnosis and Treatment

                                                                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                          HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                          Case Study 6 ndash Discussion

                                                                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                          44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                          Case Study 7 ndash Presentation

                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                          On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                          Case Study 7 ndash Presentation

                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                          Case Study 7 ndash Lab Results vs Time

                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                          Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                          Case Study 7 ndash Diagnosis and Treatment

                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                          On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                          Case Study 7 ndash Diagnosis and Treatment

                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                          DIC Take Home Messages

                                                                                                          Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                          Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                          DIC

                                                                                                          Thank you Questions

                                                                                                          • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                          • Learning Objectives
                                                                                                          • Slide Number 3
                                                                                                          • Slide Number 4
                                                                                                          • Slide Number 5
                                                                                                          • Slide Number 6
                                                                                                          • Slide Number 7
                                                                                                          • Slide Number 8
                                                                                                          • Wound Sealing
                                                                                                          • The Three Steps of Hemostasis
                                                                                                          • Vessel Wall
                                                                                                          • Slide Number 12
                                                                                                          • Slide Number 13
                                                                                                          • Platelet Structure UnactivatedActivated
                                                                                                          • Primary Hemostasis
                                                                                                          • Primary Hemostasis Assays
                                                                                                          • Slide Number 17
                                                                                                          • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                          • Slide Number 19
                                                                                                          • Coagulation factors
                                                                                                          • Coagulation Assay Mechanisms
                                                                                                          • Slide Number 22
                                                                                                          • Fibrin Formation
                                                                                                          • Slide Number 24
                                                                                                          • Fibrinolysis Overview
                                                                                                          • Fibrinolysis Overview
                                                                                                          • Slide Number 27
                                                                                                          • Fibrinolysis Releases D-dimers
                                                                                                          • Basic Pathophysiology of DIC
                                                                                                          • Disseminated Intravascular Coagulation (DIC)
                                                                                                          • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                          • Clinical Conditions Associated With DIC
                                                                                                          • Frequency of DIC in Selected Disease States
                                                                                                          • Underlying Diseases in DIC Patients
                                                                                                          • Slide Number 36
                                                                                                          • Slide Number 37
                                                                                                          • Slide Number 38
                                                                                                          • Slide Number 39
                                                                                                          • Pathophysiology of DIC
                                                                                                          • Pathogenesis of DIC in Sepsis
                                                                                                          • Host Response in Severe Sepsis
                                                                                                          • Organ Failure in Severe Sepsis
                                                                                                          • Mechanism of DIC in Organ Failure
                                                                                                          • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                          • Slide Number 47
                                                                                                          • Diverse and Opposing Effects of Thrombin
                                                                                                          • Coagulation and Fibrinolysis in DIC
                                                                                                          • Mechanism of DIC
                                                                                                          • Pathophysiology of DIC
                                                                                                          • Pathophysiology of DIC - Mechanism
                                                                                                          • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                          • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                          • Pathophysiology of Overt DIC
                                                                                                          • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                          • Slide Number 57
                                                                                                          • Slide Number 58
                                                                                                          • Slide Number 59
                                                                                                          • Slide Number 60
                                                                                                          • Slide Number 61
                                                                                                          • BREAK
                                                                                                          • Diagnostic and Management Approach for DIC
                                                                                                          • Diagnosis of DIC
                                                                                                          • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                          • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                          • Slide Number 67
                                                                                                          • Slide Number 68
                                                                                                          • British Journal of Haematology Overt DIC Score
                                                                                                          • Slide Number 70
                                                                                                          • Slide Number 71
                                                                                                          • Slide Number 72
                                                                                                          • Slide Number 73
                                                                                                          • DIC Management Goals
                                                                                                          • DIC Management and Treatment
                                                                                                          • DIC Management Strategies
                                                                                                          • Anticoagulant Factor Concentrate Treatment
                                                                                                          • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                          • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                          • D-dimer FDPs and DIC
                                                                                                          • D-Dimer and FDPs in DIC
                                                                                                          • Follow Up of DIC State of Disease
                                                                                                          • FMD-Dimer in DIC Major Differences
                                                                                                          • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                          • Slide Number 85
                                                                                                          • Slide Number 86
                                                                                                          • Comparing an Automated FM vs Manual FSP Test
                                                                                                          • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                          • Slide Number 94
                                                                                                          • Slide Number 95
                                                                                                          • Slide Number 96
                                                                                                          • Slide Number 97
                                                                                                          • Slide Number 98
                                                                                                          • Slide Number 99
                                                                                                          • DIC Case Studies
                                                                                                          • Case Study 1 - Presentation
                                                                                                          • Case Study 1 ndash Lab Results
                                                                                                          • Case Study 1 ndash Microscopy
                                                                                                          • Case Study 1 ndash Diagnosis and Therapy
                                                                                                          • Slide Number 105
                                                                                                          • Slide Number 106
                                                                                                          • Slide Number 107
                                                                                                          • Slide Number 108
                                                                                                          • Slide Number 109
                                                                                                          • Slide Number 110
                                                                                                          • Slide Number 111
                                                                                                          • Slide Number 112
                                                                                                          • Slide Number 113
                                                                                                          • Slide Number 114
                                                                                                          • Slide Number 115
                                                                                                          • Slide Number 116
                                                                                                          • Slide Number 117
                                                                                                          • Slide Number 118
                                                                                                          • Slide Number 119
                                                                                                          • Slide Number 120
                                                                                                          • Slide Number 121
                                                                                                          • Slide Number 122
                                                                                                          • Slide Number 123
                                                                                                          • Slide Number 124
                                                                                                          • Slide Number 125
                                                                                                          • DIC Take Home Messages
                                                                                                          • Slide Number 127
                                                                                                          • Slide Number 128

                                                                                                            Sub-Acute and Non-Overt DIC Clinical Findings

                                                                                                            Compensated non-overt DIC Steady low level or intermittent activation

                                                                                                            bull Compensated by increased production of coagulation components and platelets

                                                                                                            Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious

                                                                                                            Risk of decompensation leading to overt DIC

                                                                                                            Pathophysiology of Overt DIC

                                                                                                            Massive activation of coagulation and fibrinolysis

                                                                                                            Does not allow for compensatory efforts

                                                                                                            Rapid depletion of coagulation factors inhibitors and platelets

                                                                                                            Thrombosis multiple organ failures

                                                                                                            Bleeding complications and shock

                                                                                                            Physiopathology of DIC ndash Overt DIC Findings

                                                                                                            Thrombin generation

                                                                                                            Thrombosis

                                                                                                            Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                                                                                                            Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                                                                                                            Plasmin generationHemorrhage

                                                                                                            bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                                                                                                            bull Tachycardia hypotension edema

                                                                                                            Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                            Pathogenesis Pathways in DIC

                                                                                                            Cytokines

                                                                                                            TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                                                                                                            fibrin inadequateformation fibrin removal

                                                                                                            Fibrin deposition

                                                                                                            Inflammation

                                                                                                            Coagulation

                                                                                                            Stago Celebrates Lab Week 2017

                                                                                                            NA

                                                                                                            Stago 247 Educational Webinar Sites

                                                                                                            wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                                                                                                            wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                                                                                                            Stago Educational Apps

                                                                                                            HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                                                                                                            iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                                                                                                            BREAK

                                                                                                            Diagnostic and Management Approach for DIC

                                                                                                            Diagnosis of DIC

                                                                                                            Clinical diagnosis is obvious in cases of overt DIC

                                                                                                            Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                                                                                            Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                                                                                            Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                                                                                            Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                                                                                            Important to recognize simultaneous formation of thrombin and plasmin

                                                                                                            Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                                            Lab Diagnosis of DIC ndash Screening Tests

                                                                                                            Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                                            Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                                                                                            fibrinogen level) repeat testing assesses progression

                                                                                                            Screening tests not clinically specific or sensitive for DIC

                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                            Laboratory Changes in Overt DIC

                                                                                                            DIC Diagnostic Practices Over Time

                                                                                                            Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                            British Journal of Haematology Overt DIC Score

                                                                                                            Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                            ISTH Step by Step DIC Algorithm

                                                                                                            Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                                                                            US Based Validation of ISTH DIC Score

                                                                                                            When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                            Differential Diagnosis in DIC

                                                                                                            aHUS atypical hemolytic uremic syndrome

                                                                                                            HUS hemolytic uremic syndrome

                                                                                                            HIT heparin-induced thrombocytopenia

                                                                                                            ITP immune thrombocytopenic purpura

                                                                                                            TTP thrombotic thrombocytopenic purpura

                                                                                                            DIC and MAHA

                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                            lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                                                                            When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                                                                            DIC Management Goals

                                                                                                            Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                            Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                                                                            DIC Management and Treatment

                                                                                                            Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                            Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                                                                            requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                                                                            Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                                                                            DIC Management Strategies

                                                                                                            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                            Anticoagulant Factor Concentrate Treatment

                                                                                                            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                            Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                                                            Anticoagulant Factor Concentrate Treatment Trials

                                                                                                            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                            Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                                                            Markers of Thrombin amp Plasmin Generation in DIC

                                                                                                            D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                                                            Cut-off value

                                                                                                            Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                                                            degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                                                            D-dimer FDPs and DIC

                                                                                                            D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                                                            Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                                                            Follow Up of DIC State of Disease

                                                                                                            Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                                                            Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                                                            FMD-Dimer in DIC Major Differences

                                                                                                            onset of thrombosis

                                                                                                            days

                                                                                                            Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                                                            FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                                                            D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                                                            of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                                                            0

                                                                                                            20

                                                                                                            40

                                                                                                            60

                                                                                                            80

                                                                                                            100

                                                                                                            94 85 90N = 62

                                                                                                            Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                                                            Positivity of Test Results ISTH Score and Disease State

                                                                                                            Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                            Red bar positive for 2 points of DIC score

                                                                                                            Pink bar positive for 1-2 points of DIC score

                                                                                                            HT hematopoietic tumor

                                                                                                            IF infection

                                                                                                            SC solid cancer

                                                                                                            Markers in Patients with or without DIC

                                                                                                            Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                            HT hematopoietic tumorIF infectionSC solid cancer

                                                                                                            Comparing an Automated FM vs Manual FSP Test

                                                                                                            Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                                            Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                                            Automated (Mitsubishi) vs Automated (Stago)

                                                                                                            In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                                            Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                            In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                            In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                            In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                                                            Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                            No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                            Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                                                            Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                            Non Overt DIC Overt DIC

                                                                                                            AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                            Trends in Markers of DIC for Different Patients

                                                                                                            Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                            Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                            Trends in Markers of DIC for Different Patients

                                                                                                            Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                            FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                            28 day outcome survival

                                                                                                            28 day outcome death

                                                                                                            Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                            Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                            Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                            Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                            Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                            Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                            DIC Case Studies

                                                                                                            Case Study 1 - Presentation

                                                                                                            18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                            Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                            WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                            RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                            Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                            Hematocrit 195 401 ndash 510

                                                                                                            MCV 95 fL 790 ndash 922 fL

                                                                                                            MPV 12 fL 94 ndash 124 fL

                                                                                                            Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                            Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                            Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                            PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                            APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                            Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                            D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                            Case Study 1 ndash Microscopy

                                                                                                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                            Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                            Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                            DIC due to TF release by APL blasts

                                                                                                            Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                            Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                            20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                            Case Study 2 ndash Presentation

                                                                                                            TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                            PT 30 sec 113 ndash 146 sec

                                                                                                            APTT 75 sec 25 ndash 34 sec

                                                                                                            D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                            Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                            pH 728 738 to 742

                                                                                                            PaO2 570 mmHg 80-100 mmHg

                                                                                                            WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                            ALT 111 IUL 0ndash34 IUL

                                                                                                            AST 61 IUL 0ndash34 IUL

                                                                                                            BUN 303 mgdL 08-13 mgdL

                                                                                                            Case Study 2 ndash Lab Results

                                                                                                            Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                            Case Study 2 ndash Diagnosis

                                                                                                            60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                            Case Study 3 ndash Presentation

                                                                                                            TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                            PT 228 sec 113 ndash 146 sec

                                                                                                            APTT 45 sec 25 ndash 34 sec

                                                                                                            D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                            Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                            FV Normal 70-120

                                                                                                            FVII Normal 55-170

                                                                                                            FVIII Normal 60-150

                                                                                                            Protein C Normal 70-130

                                                                                                            Hb 134 gdL 14-16 gdL

                                                                                                            WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                            ALT 32 IUL 0ndash34 IUL

                                                                                                            AST 28 IUL 0ndash34 IUL

                                                                                                            BUN 09 mgdL 08-13 mgdL

                                                                                                            Case Study 3 ndash Lab Results

                                                                                                            Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                            Case Study 3 ndash Diagnosis and Therapy

                                                                                                            Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                            Case Study 4 ndash Presentation

                                                                                                            TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                            PT 28 sec 113 ndash 146 sec

                                                                                                            APTT 71 sec 25 ndash 34 sec

                                                                                                            D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                            Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                            FV Normal 70-120

                                                                                                            FVII Normal 55-170

                                                                                                            FVIII Normal 60-150

                                                                                                            Protein C Normal 70-130

                                                                                                            Hb 158 gdL 14-16 gdL

                                                                                                            WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                            ALT 60 IUL 0ndash34 IUL

                                                                                                            AST 47 IUL 0ndash34 IUL

                                                                                                            BUN 38 mgdL 08-13 mgdL

                                                                                                            Case Study 4 ndash Lab Results

                                                                                                            Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                            Case Study 4 ndash Diagnosis

                                                                                                            55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                            Case Study 5 ndash Presentation

                                                                                                            Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                            Case Study 5 ndash Lab Results and Time Course

                                                                                                            Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                            TEST RESULT REFERENCE RANGE

                                                                                                            Platelet count 33 x 109L 150-450 x 109L

                                                                                                            PT 215 sec 103 ndash 128 sec

                                                                                                            APTT 44 sec 26 ndash 36 sec

                                                                                                            D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                            Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                            FII FV FVIII Low Not reported (NR)

                                                                                                            FVII FIX FX vWF Normal NR

                                                                                                            Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                            DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                            dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                            (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                            (D) Illustration demonstrating repair

                                                                                                            Case Study 5 ndash Diagnosis and Treatment

                                                                                                            Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                            29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                            Case Study 6 ndash Presentation

                                                                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                            Case Study 6 ndash Lab Results

                                                                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                            TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                            PT 63 sec gt control 113 ndash 146 sec

                                                                                                            INR 658 1 ndash 125

                                                                                                            APTT 80 sec gt control 25 ndash 34 sec

                                                                                                            D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                            Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                            Albumin 28 gdL NR

                                                                                                            Hb 58 gdL NR

                                                                                                            LDH 1196 UL NR

                                                                                                            SGPT 144 IU NR

                                                                                                            SGOT 88 IU NR

                                                                                                            Bilirubin 32 mgdL NR

                                                                                                            DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                            day postop

                                                                                                            Case Study 6 ndash Diagnosis and Treatment

                                                                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                            HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                            Case Study 6 ndash Discussion

                                                                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                            44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                            Case Study 7 ndash Presentation

                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                            On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                            Case Study 7 ndash Presentation

                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                            Case Study 7 ndash Lab Results vs Time

                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                            Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                            Case Study 7 ndash Diagnosis and Treatment

                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                            On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                            Case Study 7 ndash Diagnosis and Treatment

                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                            DIC Take Home Messages

                                                                                                            Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                            Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                            DIC

                                                                                                            Thank you Questions

                                                                                                            • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                            • Learning Objectives
                                                                                                            • Slide Number 3
                                                                                                            • Slide Number 4
                                                                                                            • Slide Number 5
                                                                                                            • Slide Number 6
                                                                                                            • Slide Number 7
                                                                                                            • Slide Number 8
                                                                                                            • Wound Sealing
                                                                                                            • The Three Steps of Hemostasis
                                                                                                            • Vessel Wall
                                                                                                            • Slide Number 12
                                                                                                            • Slide Number 13
                                                                                                            • Platelet Structure UnactivatedActivated
                                                                                                            • Primary Hemostasis
                                                                                                            • Primary Hemostasis Assays
                                                                                                            • Slide Number 17
                                                                                                            • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                            • Slide Number 19
                                                                                                            • Coagulation factors
                                                                                                            • Coagulation Assay Mechanisms
                                                                                                            • Slide Number 22
                                                                                                            • Fibrin Formation
                                                                                                            • Slide Number 24
                                                                                                            • Fibrinolysis Overview
                                                                                                            • Fibrinolysis Overview
                                                                                                            • Slide Number 27
                                                                                                            • Fibrinolysis Releases D-dimers
                                                                                                            • Basic Pathophysiology of DIC
                                                                                                            • Disseminated Intravascular Coagulation (DIC)
                                                                                                            • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                            • Clinical Conditions Associated With DIC
                                                                                                            • Frequency of DIC in Selected Disease States
                                                                                                            • Underlying Diseases in DIC Patients
                                                                                                            • Slide Number 36
                                                                                                            • Slide Number 37
                                                                                                            • Slide Number 38
                                                                                                            • Slide Number 39
                                                                                                            • Pathophysiology of DIC
                                                                                                            • Pathogenesis of DIC in Sepsis
                                                                                                            • Host Response in Severe Sepsis
                                                                                                            • Organ Failure in Severe Sepsis
                                                                                                            • Mechanism of DIC in Organ Failure
                                                                                                            • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                            • Slide Number 47
                                                                                                            • Diverse and Opposing Effects of Thrombin
                                                                                                            • Coagulation and Fibrinolysis in DIC
                                                                                                            • Mechanism of DIC
                                                                                                            • Pathophysiology of DIC
                                                                                                            • Pathophysiology of DIC - Mechanism
                                                                                                            • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                            • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                            • Pathophysiology of Overt DIC
                                                                                                            • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                            • Slide Number 57
                                                                                                            • Slide Number 58
                                                                                                            • Slide Number 59
                                                                                                            • Slide Number 60
                                                                                                            • Slide Number 61
                                                                                                            • BREAK
                                                                                                            • Diagnostic and Management Approach for DIC
                                                                                                            • Diagnosis of DIC
                                                                                                            • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                            • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                            • Slide Number 67
                                                                                                            • Slide Number 68
                                                                                                            • British Journal of Haematology Overt DIC Score
                                                                                                            • Slide Number 70
                                                                                                            • Slide Number 71
                                                                                                            • Slide Number 72
                                                                                                            • Slide Number 73
                                                                                                            • DIC Management Goals
                                                                                                            • DIC Management and Treatment
                                                                                                            • DIC Management Strategies
                                                                                                            • Anticoagulant Factor Concentrate Treatment
                                                                                                            • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                            • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                            • D-dimer FDPs and DIC
                                                                                                            • D-Dimer and FDPs in DIC
                                                                                                            • Follow Up of DIC State of Disease
                                                                                                            • FMD-Dimer in DIC Major Differences
                                                                                                            • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                            • Slide Number 85
                                                                                                            • Slide Number 86
                                                                                                            • Comparing an Automated FM vs Manual FSP Test
                                                                                                            • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                            • Slide Number 94
                                                                                                            • Slide Number 95
                                                                                                            • Slide Number 96
                                                                                                            • Slide Number 97
                                                                                                            • Slide Number 98
                                                                                                            • Slide Number 99
                                                                                                            • DIC Case Studies
                                                                                                            • Case Study 1 - Presentation
                                                                                                            • Case Study 1 ndash Lab Results
                                                                                                            • Case Study 1 ndash Microscopy
                                                                                                            • Case Study 1 ndash Diagnosis and Therapy
                                                                                                            • Slide Number 105
                                                                                                            • Slide Number 106
                                                                                                            • Slide Number 107
                                                                                                            • Slide Number 108
                                                                                                            • Slide Number 109
                                                                                                            • Slide Number 110
                                                                                                            • Slide Number 111
                                                                                                            • Slide Number 112
                                                                                                            • Slide Number 113
                                                                                                            • Slide Number 114
                                                                                                            • Slide Number 115
                                                                                                            • Slide Number 116
                                                                                                            • Slide Number 117
                                                                                                            • Slide Number 118
                                                                                                            • Slide Number 119
                                                                                                            • Slide Number 120
                                                                                                            • Slide Number 121
                                                                                                            • Slide Number 122
                                                                                                            • Slide Number 123
                                                                                                            • Slide Number 124
                                                                                                            • Slide Number 125
                                                                                                            • DIC Take Home Messages
                                                                                                            • Slide Number 127
                                                                                                            • Slide Number 128

                                                                                                              Pathophysiology of Overt DIC

                                                                                                              Massive activation of coagulation and fibrinolysis

                                                                                                              Does not allow for compensatory efforts

                                                                                                              Rapid depletion of coagulation factors inhibitors and platelets

                                                                                                              Thrombosis multiple organ failures

                                                                                                              Bleeding complications and shock

                                                                                                              Physiopathology of DIC ndash Overt DIC Findings

                                                                                                              Thrombin generation

                                                                                                              Thrombosis

                                                                                                              Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                                                                                                              Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                                                                                                              Plasmin generationHemorrhage

                                                                                                              bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                                                                                                              bull Tachycardia hypotension edema

                                                                                                              Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                              Pathogenesis Pathways in DIC

                                                                                                              Cytokines

                                                                                                              TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                                                                                                              fibrin inadequateformation fibrin removal

                                                                                                              Fibrin deposition

                                                                                                              Inflammation

                                                                                                              Coagulation

                                                                                                              Stago Celebrates Lab Week 2017

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                                                                                                              Stago 247 Educational Webinar Sites

                                                                                                              wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                                                                                                              wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                                                                                                              Stago Educational Apps

                                                                                                              HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                                                                                                              iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                                                                                                              BREAK

                                                                                                              Diagnostic and Management Approach for DIC

                                                                                                              Diagnosis of DIC

                                                                                                              Clinical diagnosis is obvious in cases of overt DIC

                                                                                                              Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                                                                                              Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                                                                                              Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                                                                                              Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                                                                                              Important to recognize simultaneous formation of thrombin and plasmin

                                                                                                              Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                                              Lab Diagnosis of DIC ndash Screening Tests

                                                                                                              Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                                              Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                                                                                              fibrinogen level) repeat testing assesses progression

                                                                                                              Screening tests not clinically specific or sensitive for DIC

                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                              Laboratory Changes in Overt DIC

                                                                                                              DIC Diagnostic Practices Over Time

                                                                                                              Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                              British Journal of Haematology Overt DIC Score

                                                                                                              Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                              ISTH Step by Step DIC Algorithm

                                                                                                              Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                                                                              US Based Validation of ISTH DIC Score

                                                                                                              When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                              Differential Diagnosis in DIC

                                                                                                              aHUS atypical hemolytic uremic syndrome

                                                                                                              HUS hemolytic uremic syndrome

                                                                                                              HIT heparin-induced thrombocytopenia

                                                                                                              ITP immune thrombocytopenic purpura

                                                                                                              TTP thrombotic thrombocytopenic purpura

                                                                                                              DIC and MAHA

                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                              lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                                                                              When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                                                                              DIC Management Goals

                                                                                                              Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                              Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                                                                              DIC Management and Treatment

                                                                                                              Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                              Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                                                                              requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                                                                              Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                                                                              DIC Management Strategies

                                                                                                              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                              Anticoagulant Factor Concentrate Treatment

                                                                                                              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                              Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                                                              Anticoagulant Factor Concentrate Treatment Trials

                                                                                                              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                              Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                                                              Markers of Thrombin amp Plasmin Generation in DIC

                                                                                                              D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                                                              Cut-off value

                                                                                                              Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                                                              degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                                                              D-dimer FDPs and DIC

                                                                                                              D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                                                              Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                                                              Follow Up of DIC State of Disease

                                                                                                              Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                                                              Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                                                              FMD-Dimer in DIC Major Differences

                                                                                                              onset of thrombosis

                                                                                                              days

                                                                                                              Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                                                              FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                                                              D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                                                              of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                                                              0

                                                                                                              20

                                                                                                              40

                                                                                                              60

                                                                                                              80

                                                                                                              100

                                                                                                              94 85 90N = 62

                                                                                                              Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                                                              Positivity of Test Results ISTH Score and Disease State

                                                                                                              Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                              Red bar positive for 2 points of DIC score

                                                                                                              Pink bar positive for 1-2 points of DIC score

                                                                                                              HT hematopoietic tumor

                                                                                                              IF infection

                                                                                                              SC solid cancer

                                                                                                              Markers in Patients with or without DIC

                                                                                                              Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                              HT hematopoietic tumorIF infectionSC solid cancer

                                                                                                              Comparing an Automated FM vs Manual FSP Test

                                                                                                              Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                                              Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                                              Automated (Mitsubishi) vs Automated (Stago)

                                                                                                              In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                                              Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                              In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                              In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                              In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                                                              Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                              No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                              Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                                                              Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                              Non Overt DIC Overt DIC

                                                                                                              AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                              Trends in Markers of DIC for Different Patients

                                                                                                              Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                              Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                              Trends in Markers of DIC for Different Patients

                                                                                                              Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                              FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                              28 day outcome survival

                                                                                                              28 day outcome death

                                                                                                              Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                              Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                              Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                              Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                              Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                              Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                              DIC Case Studies

                                                                                                              Case Study 1 - Presentation

                                                                                                              18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                              Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                              WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                              RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                              Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                              Hematocrit 195 401 ndash 510

                                                                                                              MCV 95 fL 790 ndash 922 fL

                                                                                                              MPV 12 fL 94 ndash 124 fL

                                                                                                              Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                              Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                              Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                              PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                              APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                              Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                              D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                              Case Study 1 ndash Microscopy

                                                                                                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                              Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                              Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                              DIC due to TF release by APL blasts

                                                                                                              Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                              Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                              20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                              Case Study 2 ndash Presentation

                                                                                                              TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                              PT 30 sec 113 ndash 146 sec

                                                                                                              APTT 75 sec 25 ndash 34 sec

                                                                                                              D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                              Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                              pH 728 738 to 742

                                                                                                              PaO2 570 mmHg 80-100 mmHg

                                                                                                              WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                              ALT 111 IUL 0ndash34 IUL

                                                                                                              AST 61 IUL 0ndash34 IUL

                                                                                                              BUN 303 mgdL 08-13 mgdL

                                                                                                              Case Study 2 ndash Lab Results

                                                                                                              Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                              Case Study 2 ndash Diagnosis

                                                                                                              60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                              Case Study 3 ndash Presentation

                                                                                                              TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                              PT 228 sec 113 ndash 146 sec

                                                                                                              APTT 45 sec 25 ndash 34 sec

                                                                                                              D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                              Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                              FV Normal 70-120

                                                                                                              FVII Normal 55-170

                                                                                                              FVIII Normal 60-150

                                                                                                              Protein C Normal 70-130

                                                                                                              Hb 134 gdL 14-16 gdL

                                                                                                              WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                              ALT 32 IUL 0ndash34 IUL

                                                                                                              AST 28 IUL 0ndash34 IUL

                                                                                                              BUN 09 mgdL 08-13 mgdL

                                                                                                              Case Study 3 ndash Lab Results

                                                                                                              Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                              Case Study 3 ndash Diagnosis and Therapy

                                                                                                              Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                              Case Study 4 ndash Presentation

                                                                                                              TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                              PT 28 sec 113 ndash 146 sec

                                                                                                              APTT 71 sec 25 ndash 34 sec

                                                                                                              D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                              Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                              FV Normal 70-120

                                                                                                              FVII Normal 55-170

                                                                                                              FVIII Normal 60-150

                                                                                                              Protein C Normal 70-130

                                                                                                              Hb 158 gdL 14-16 gdL

                                                                                                              WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                              ALT 60 IUL 0ndash34 IUL

                                                                                                              AST 47 IUL 0ndash34 IUL

                                                                                                              BUN 38 mgdL 08-13 mgdL

                                                                                                              Case Study 4 ndash Lab Results

                                                                                                              Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                              Case Study 4 ndash Diagnosis

                                                                                                              55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                              Case Study 5 ndash Presentation

                                                                                                              Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                              Case Study 5 ndash Lab Results and Time Course

                                                                                                              Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                              TEST RESULT REFERENCE RANGE

                                                                                                              Platelet count 33 x 109L 150-450 x 109L

                                                                                                              PT 215 sec 103 ndash 128 sec

                                                                                                              APTT 44 sec 26 ndash 36 sec

                                                                                                              D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                              Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                              FII FV FVIII Low Not reported (NR)

                                                                                                              FVII FIX FX vWF Normal NR

                                                                                                              Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                              DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                              dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                              (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                              (D) Illustration demonstrating repair

                                                                                                              Case Study 5 ndash Diagnosis and Treatment

                                                                                                              Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                              29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                              Case Study 6 ndash Presentation

                                                                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                              Case Study 6 ndash Lab Results

                                                                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                              TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                              PT 63 sec gt control 113 ndash 146 sec

                                                                                                              INR 658 1 ndash 125

                                                                                                              APTT 80 sec gt control 25 ndash 34 sec

                                                                                                              D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                              Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                              Albumin 28 gdL NR

                                                                                                              Hb 58 gdL NR

                                                                                                              LDH 1196 UL NR

                                                                                                              SGPT 144 IU NR

                                                                                                              SGOT 88 IU NR

                                                                                                              Bilirubin 32 mgdL NR

                                                                                                              DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                              day postop

                                                                                                              Case Study 6 ndash Diagnosis and Treatment

                                                                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                              HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                              Case Study 6 ndash Discussion

                                                                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                              44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                              Case Study 7 ndash Presentation

                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                              On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                              Case Study 7 ndash Presentation

                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                              Case Study 7 ndash Lab Results vs Time

                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                              Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                              Case Study 7 ndash Diagnosis and Treatment

                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                              On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                              Case Study 7 ndash Diagnosis and Treatment

                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                              DIC Take Home Messages

                                                                                                              Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                              Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                              DIC

                                                                                                              Thank you Questions

                                                                                                              • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                              • Learning Objectives
                                                                                                              • Slide Number 3
                                                                                                              • Slide Number 4
                                                                                                              • Slide Number 5
                                                                                                              • Slide Number 6
                                                                                                              • Slide Number 7
                                                                                                              • Slide Number 8
                                                                                                              • Wound Sealing
                                                                                                              • The Three Steps of Hemostasis
                                                                                                              • Vessel Wall
                                                                                                              • Slide Number 12
                                                                                                              • Slide Number 13
                                                                                                              • Platelet Structure UnactivatedActivated
                                                                                                              • Primary Hemostasis
                                                                                                              • Primary Hemostasis Assays
                                                                                                              • Slide Number 17
                                                                                                              • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                              • Slide Number 19
                                                                                                              • Coagulation factors
                                                                                                              • Coagulation Assay Mechanisms
                                                                                                              • Slide Number 22
                                                                                                              • Fibrin Formation
                                                                                                              • Slide Number 24
                                                                                                              • Fibrinolysis Overview
                                                                                                              • Fibrinolysis Overview
                                                                                                              • Slide Number 27
                                                                                                              • Fibrinolysis Releases D-dimers
                                                                                                              • Basic Pathophysiology of DIC
                                                                                                              • Disseminated Intravascular Coagulation (DIC)
                                                                                                              • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                              • Clinical Conditions Associated With DIC
                                                                                                              • Frequency of DIC in Selected Disease States
                                                                                                              • Underlying Diseases in DIC Patients
                                                                                                              • Slide Number 36
                                                                                                              • Slide Number 37
                                                                                                              • Slide Number 38
                                                                                                              • Slide Number 39
                                                                                                              • Pathophysiology of DIC
                                                                                                              • Pathogenesis of DIC in Sepsis
                                                                                                              • Host Response in Severe Sepsis
                                                                                                              • Organ Failure in Severe Sepsis
                                                                                                              • Mechanism of DIC in Organ Failure
                                                                                                              • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                              • Slide Number 47
                                                                                                              • Diverse and Opposing Effects of Thrombin
                                                                                                              • Coagulation and Fibrinolysis in DIC
                                                                                                              • Mechanism of DIC
                                                                                                              • Pathophysiology of DIC
                                                                                                              • Pathophysiology of DIC - Mechanism
                                                                                                              • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                              • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                              • Pathophysiology of Overt DIC
                                                                                                              • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                              • Slide Number 57
                                                                                                              • Slide Number 58
                                                                                                              • Slide Number 59
                                                                                                              • Slide Number 60
                                                                                                              • Slide Number 61
                                                                                                              • BREAK
                                                                                                              • Diagnostic and Management Approach for DIC
                                                                                                              • Diagnosis of DIC
                                                                                                              • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                              • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                              • Slide Number 67
                                                                                                              • Slide Number 68
                                                                                                              • British Journal of Haematology Overt DIC Score
                                                                                                              • Slide Number 70
                                                                                                              • Slide Number 71
                                                                                                              • Slide Number 72
                                                                                                              • Slide Number 73
                                                                                                              • DIC Management Goals
                                                                                                              • DIC Management and Treatment
                                                                                                              • DIC Management Strategies
                                                                                                              • Anticoagulant Factor Concentrate Treatment
                                                                                                              • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                              • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                              • D-dimer FDPs and DIC
                                                                                                              • D-Dimer and FDPs in DIC
                                                                                                              • Follow Up of DIC State of Disease
                                                                                                              • FMD-Dimer in DIC Major Differences
                                                                                                              • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                              • Slide Number 85
                                                                                                              • Slide Number 86
                                                                                                              • Comparing an Automated FM vs Manual FSP Test
                                                                                                              • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                              • Slide Number 94
                                                                                                              • Slide Number 95
                                                                                                              • Slide Number 96
                                                                                                              • Slide Number 97
                                                                                                              • Slide Number 98
                                                                                                              • Slide Number 99
                                                                                                              • DIC Case Studies
                                                                                                              • Case Study 1 - Presentation
                                                                                                              • Case Study 1 ndash Lab Results
                                                                                                              • Case Study 1 ndash Microscopy
                                                                                                              • Case Study 1 ndash Diagnosis and Therapy
                                                                                                              • Slide Number 105
                                                                                                              • Slide Number 106
                                                                                                              • Slide Number 107
                                                                                                              • Slide Number 108
                                                                                                              • Slide Number 109
                                                                                                              • Slide Number 110
                                                                                                              • Slide Number 111
                                                                                                              • Slide Number 112
                                                                                                              • Slide Number 113
                                                                                                              • Slide Number 114
                                                                                                              • Slide Number 115
                                                                                                              • Slide Number 116
                                                                                                              • Slide Number 117
                                                                                                              • Slide Number 118
                                                                                                              • Slide Number 119
                                                                                                              • Slide Number 120
                                                                                                              • Slide Number 121
                                                                                                              • Slide Number 122
                                                                                                              • Slide Number 123
                                                                                                              • Slide Number 124
                                                                                                              • Slide Number 125
                                                                                                              • DIC Take Home Messages
                                                                                                              • Slide Number 127
                                                                                                              • Slide Number 128

                                                                                                                Physiopathology of DIC ndash Overt DIC Findings

                                                                                                                Thrombin generation

                                                                                                                Thrombosis

                                                                                                                Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema

                                                                                                                Cytokine and kinin generation (shock)bull Tachycardia hypotension edema

                                                                                                                Plasmin generationHemorrhage

                                                                                                                bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds

                                                                                                                bull Tachycardia hypotension edema

                                                                                                                Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                                Pathogenesis Pathways in DIC

                                                                                                                Cytokines

                                                                                                                TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                                                                                                                fibrin inadequateformation fibrin removal

                                                                                                                Fibrin deposition

                                                                                                                Inflammation

                                                                                                                Coagulation

                                                                                                                Stago Celebrates Lab Week 2017

                                                                                                                NA

                                                                                                                Stago 247 Educational Webinar Sites

                                                                                                                wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                                                                                                                wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                                                                                                                Stago Educational Apps

                                                                                                                HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                                                                                                                iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                                                                                                                BREAK

                                                                                                                Diagnostic and Management Approach for DIC

                                                                                                                Diagnosis of DIC

                                                                                                                Clinical diagnosis is obvious in cases of overt DIC

                                                                                                                Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                                                                                                Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                                                                                                Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                                                                                                Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                                                                                                Important to recognize simultaneous formation of thrombin and plasmin

                                                                                                                Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                                                Lab Diagnosis of DIC ndash Screening Tests

                                                                                                                Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                                                Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                                                                                                fibrinogen level) repeat testing assesses progression

                                                                                                                Screening tests not clinically specific or sensitive for DIC

                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                Laboratory Changes in Overt DIC

                                                                                                                DIC Diagnostic Practices Over Time

                                                                                                                Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                British Journal of Haematology Overt DIC Score

                                                                                                                Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                ISTH Step by Step DIC Algorithm

                                                                                                                Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                                                                                US Based Validation of ISTH DIC Score

                                                                                                                When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                Differential Diagnosis in DIC

                                                                                                                aHUS atypical hemolytic uremic syndrome

                                                                                                                HUS hemolytic uremic syndrome

                                                                                                                HIT heparin-induced thrombocytopenia

                                                                                                                ITP immune thrombocytopenic purpura

                                                                                                                TTP thrombotic thrombocytopenic purpura

                                                                                                                DIC and MAHA

                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                                                                                When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                                                                                DIC Management Goals

                                                                                                                Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                                Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                                                                                DIC Management and Treatment

                                                                                                                Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                                Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                                                                                requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                                                                                Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                                                                                DIC Management Strategies

                                                                                                                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                Anticoagulant Factor Concentrate Treatment

                                                                                                                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                                                                Anticoagulant Factor Concentrate Treatment Trials

                                                                                                                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                                                                Markers of Thrombin amp Plasmin Generation in DIC

                                                                                                                D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                                                                Cut-off value

                                                                                                                Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                                                                degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                                                                D-dimer FDPs and DIC

                                                                                                                D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                                                                Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                                                                Follow Up of DIC State of Disease

                                                                                                                Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                                                                Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                                                                FMD-Dimer in DIC Major Differences

                                                                                                                onset of thrombosis

                                                                                                                days

                                                                                                                Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                                                                FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                                                                D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                                                                of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                                                                0

                                                                                                                20

                                                                                                                40

                                                                                                                60

                                                                                                                80

                                                                                                                100

                                                                                                                94 85 90N = 62

                                                                                                                Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                                                                Positivity of Test Results ISTH Score and Disease State

                                                                                                                Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                Red bar positive for 2 points of DIC score

                                                                                                                Pink bar positive for 1-2 points of DIC score

                                                                                                                HT hematopoietic tumor

                                                                                                                IF infection

                                                                                                                SC solid cancer

                                                                                                                Markers in Patients with or without DIC

                                                                                                                Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                HT hematopoietic tumorIF infectionSC solid cancer

                                                                                                                Comparing an Automated FM vs Manual FSP Test

                                                                                                                Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                                                Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                                                Automated (Mitsubishi) vs Automated (Stago)

                                                                                                                In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                                                Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                                Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                Non Overt DIC Overt DIC

                                                                                                                AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                                Trends in Markers of DIC for Different Patients

                                                                                                                Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                                Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                                Trends in Markers of DIC for Different Patients

                                                                                                                Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                                28 day outcome survival

                                                                                                                28 day outcome death

                                                                                                                Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                                Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                                DIC Case Studies

                                                                                                                Case Study 1 - Presentation

                                                                                                                18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                Hematocrit 195 401 ndash 510

                                                                                                                MCV 95 fL 790 ndash 922 fL

                                                                                                                MPV 12 fL 94 ndash 124 fL

                                                                                                                Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                Case Study 1 ndash Microscopy

                                                                                                                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                DIC due to TF release by APL blasts

                                                                                                                Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                Case Study 2 ndash Presentation

                                                                                                                TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                PT 30 sec 113 ndash 146 sec

                                                                                                                APTT 75 sec 25 ndash 34 sec

                                                                                                                D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                pH 728 738 to 742

                                                                                                                PaO2 570 mmHg 80-100 mmHg

                                                                                                                WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                ALT 111 IUL 0ndash34 IUL

                                                                                                                AST 61 IUL 0ndash34 IUL

                                                                                                                BUN 303 mgdL 08-13 mgdL

                                                                                                                Case Study 2 ndash Lab Results

                                                                                                                Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                Case Study 2 ndash Diagnosis

                                                                                                                60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                Case Study 3 ndash Presentation

                                                                                                                TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                PT 228 sec 113 ndash 146 sec

                                                                                                                APTT 45 sec 25 ndash 34 sec

                                                                                                                D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                FV Normal 70-120

                                                                                                                FVII Normal 55-170

                                                                                                                FVIII Normal 60-150

                                                                                                                Protein C Normal 70-130

                                                                                                                Hb 134 gdL 14-16 gdL

                                                                                                                WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                ALT 32 IUL 0ndash34 IUL

                                                                                                                AST 28 IUL 0ndash34 IUL

                                                                                                                BUN 09 mgdL 08-13 mgdL

                                                                                                                Case Study 3 ndash Lab Results

                                                                                                                Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                Case Study 3 ndash Diagnosis and Therapy

                                                                                                                Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                Case Study 4 ndash Presentation

                                                                                                                TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                PT 28 sec 113 ndash 146 sec

                                                                                                                APTT 71 sec 25 ndash 34 sec

                                                                                                                D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                FV Normal 70-120

                                                                                                                FVII Normal 55-170

                                                                                                                FVIII Normal 60-150

                                                                                                                Protein C Normal 70-130

                                                                                                                Hb 158 gdL 14-16 gdL

                                                                                                                WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                ALT 60 IUL 0ndash34 IUL

                                                                                                                AST 47 IUL 0ndash34 IUL

                                                                                                                BUN 38 mgdL 08-13 mgdL

                                                                                                                Case Study 4 ndash Lab Results

                                                                                                                Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                Case Study 4 ndash Diagnosis

                                                                                                                55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                Case Study 5 ndash Presentation

                                                                                                                Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                Case Study 5 ndash Lab Results and Time Course

                                                                                                                Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                TEST RESULT REFERENCE RANGE

                                                                                                                Platelet count 33 x 109L 150-450 x 109L

                                                                                                                PT 215 sec 103 ndash 128 sec

                                                                                                                APTT 44 sec 26 ndash 36 sec

                                                                                                                D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                FII FV FVIII Low Not reported (NR)

                                                                                                                FVII FIX FX vWF Normal NR

                                                                                                                Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                (D) Illustration demonstrating repair

                                                                                                                Case Study 5 ndash Diagnosis and Treatment

                                                                                                                Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                Case Study 6 ndash Presentation

                                                                                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                Case Study 6 ndash Lab Results

                                                                                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                PT 63 sec gt control 113 ndash 146 sec

                                                                                                                INR 658 1 ndash 125

                                                                                                                APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                Albumin 28 gdL NR

                                                                                                                Hb 58 gdL NR

                                                                                                                LDH 1196 UL NR

                                                                                                                SGPT 144 IU NR

                                                                                                                SGOT 88 IU NR

                                                                                                                Bilirubin 32 mgdL NR

                                                                                                                DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                day postop

                                                                                                                Case Study 6 ndash Diagnosis and Treatment

                                                                                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                Case Study 6 ndash Discussion

                                                                                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                Case Study 7 ndash Presentation

                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                Case Study 7 ndash Presentation

                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                Case Study 7 ndash Lab Results vs Time

                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                Case Study 7 ndash Diagnosis and Treatment

                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                Case Study 7 ndash Diagnosis and Treatment

                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                DIC Take Home Messages

                                                                                                                Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                DIC

                                                                                                                Thank you Questions

                                                                                                                • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                • Learning Objectives
                                                                                                                • Slide Number 3
                                                                                                                • Slide Number 4
                                                                                                                • Slide Number 5
                                                                                                                • Slide Number 6
                                                                                                                • Slide Number 7
                                                                                                                • Slide Number 8
                                                                                                                • Wound Sealing
                                                                                                                • The Three Steps of Hemostasis
                                                                                                                • Vessel Wall
                                                                                                                • Slide Number 12
                                                                                                                • Slide Number 13
                                                                                                                • Platelet Structure UnactivatedActivated
                                                                                                                • Primary Hemostasis
                                                                                                                • Primary Hemostasis Assays
                                                                                                                • Slide Number 17
                                                                                                                • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                • Slide Number 19
                                                                                                                • Coagulation factors
                                                                                                                • Coagulation Assay Mechanisms
                                                                                                                • Slide Number 22
                                                                                                                • Fibrin Formation
                                                                                                                • Slide Number 24
                                                                                                                • Fibrinolysis Overview
                                                                                                                • Fibrinolysis Overview
                                                                                                                • Slide Number 27
                                                                                                                • Fibrinolysis Releases D-dimers
                                                                                                                • Basic Pathophysiology of DIC
                                                                                                                • Disseminated Intravascular Coagulation (DIC)
                                                                                                                • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                • Clinical Conditions Associated With DIC
                                                                                                                • Frequency of DIC in Selected Disease States
                                                                                                                • Underlying Diseases in DIC Patients
                                                                                                                • Slide Number 36
                                                                                                                • Slide Number 37
                                                                                                                • Slide Number 38
                                                                                                                • Slide Number 39
                                                                                                                • Pathophysiology of DIC
                                                                                                                • Pathogenesis of DIC in Sepsis
                                                                                                                • Host Response in Severe Sepsis
                                                                                                                • Organ Failure in Severe Sepsis
                                                                                                                • Mechanism of DIC in Organ Failure
                                                                                                                • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                • Slide Number 47
                                                                                                                • Diverse and Opposing Effects of Thrombin
                                                                                                                • Coagulation and Fibrinolysis in DIC
                                                                                                                • Mechanism of DIC
                                                                                                                • Pathophysiology of DIC
                                                                                                                • Pathophysiology of DIC - Mechanism
                                                                                                                • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                • Pathophysiology of Overt DIC
                                                                                                                • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                • Slide Number 57
                                                                                                                • Slide Number 58
                                                                                                                • Slide Number 59
                                                                                                                • Slide Number 60
                                                                                                                • Slide Number 61
                                                                                                                • BREAK
                                                                                                                • Diagnostic and Management Approach for DIC
                                                                                                                • Diagnosis of DIC
                                                                                                                • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                • Slide Number 67
                                                                                                                • Slide Number 68
                                                                                                                • British Journal of Haematology Overt DIC Score
                                                                                                                • Slide Number 70
                                                                                                                • Slide Number 71
                                                                                                                • Slide Number 72
                                                                                                                • Slide Number 73
                                                                                                                • DIC Management Goals
                                                                                                                • DIC Management and Treatment
                                                                                                                • DIC Management Strategies
                                                                                                                • Anticoagulant Factor Concentrate Treatment
                                                                                                                • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                • D-dimer FDPs and DIC
                                                                                                                • D-Dimer and FDPs in DIC
                                                                                                                • Follow Up of DIC State of Disease
                                                                                                                • FMD-Dimer in DIC Major Differences
                                                                                                                • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                • Slide Number 85
                                                                                                                • Slide Number 86
                                                                                                                • Comparing an Automated FM vs Manual FSP Test
                                                                                                                • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                • Slide Number 94
                                                                                                                • Slide Number 95
                                                                                                                • Slide Number 96
                                                                                                                • Slide Number 97
                                                                                                                • Slide Number 98
                                                                                                                • Slide Number 99
                                                                                                                • DIC Case Studies
                                                                                                                • Case Study 1 - Presentation
                                                                                                                • Case Study 1 ndash Lab Results
                                                                                                                • Case Study 1 ndash Microscopy
                                                                                                                • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                • Slide Number 105
                                                                                                                • Slide Number 106
                                                                                                                • Slide Number 107
                                                                                                                • Slide Number 108
                                                                                                                • Slide Number 109
                                                                                                                • Slide Number 110
                                                                                                                • Slide Number 111
                                                                                                                • Slide Number 112
                                                                                                                • Slide Number 113
                                                                                                                • Slide Number 114
                                                                                                                • Slide Number 115
                                                                                                                • Slide Number 116
                                                                                                                • Slide Number 117
                                                                                                                • Slide Number 118
                                                                                                                • Slide Number 119
                                                                                                                • Slide Number 120
                                                                                                                • Slide Number 121
                                                                                                                • Slide Number 122
                                                                                                                • Slide Number 123
                                                                                                                • Slide Number 124
                                                                                                                • Slide Number 125
                                                                                                                • DIC Take Home Messages
                                                                                                                • Slide Number 127
                                                                                                                • Slide Number 128

                                                                                                                  Pathogenesis Pathways in DIC

                                                                                                                  Cytokines

                                                                                                                  TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency

                                                                                                                  fibrin inadequateformation fibrin removal

                                                                                                                  Fibrin deposition

                                                                                                                  Inflammation

                                                                                                                  Coagulation

                                                                                                                  Stago Celebrates Lab Week 2017

                                                                                                                  NA

                                                                                                                  Stago 247 Educational Webinar Sites

                                                                                                                  wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                                                                                                                  wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                                                                                                                  Stago Educational Apps

                                                                                                                  HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                                                                                                                  iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                                                                                                                  BREAK

                                                                                                                  Diagnostic and Management Approach for DIC

                                                                                                                  Diagnosis of DIC

                                                                                                                  Clinical diagnosis is obvious in cases of overt DIC

                                                                                                                  Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                                                                                                  Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                                                                                                  Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                                                                                                  Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                                                                                                  Important to recognize simultaneous formation of thrombin and plasmin

                                                                                                                  Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                                                  Lab Diagnosis of DIC ndash Screening Tests

                                                                                                                  Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                                                  Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                                                                                                  fibrinogen level) repeat testing assesses progression

                                                                                                                  Screening tests not clinically specific or sensitive for DIC

                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                  Laboratory Changes in Overt DIC

                                                                                                                  DIC Diagnostic Practices Over Time

                                                                                                                  Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                  British Journal of Haematology Overt DIC Score

                                                                                                                  Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                  ISTH Step by Step DIC Algorithm

                                                                                                                  Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                                                                                  US Based Validation of ISTH DIC Score

                                                                                                                  When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                  Differential Diagnosis in DIC

                                                                                                                  aHUS atypical hemolytic uremic syndrome

                                                                                                                  HUS hemolytic uremic syndrome

                                                                                                                  HIT heparin-induced thrombocytopenia

                                                                                                                  ITP immune thrombocytopenic purpura

                                                                                                                  TTP thrombotic thrombocytopenic purpura

                                                                                                                  DIC and MAHA

                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                  lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                                                                                  When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                                                                                  DIC Management Goals

                                                                                                                  Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                                  Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                                                                                  DIC Management and Treatment

                                                                                                                  Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                                  Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                                                                                  requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                                                                                  Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                                                                                  DIC Management Strategies

                                                                                                                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                  Anticoagulant Factor Concentrate Treatment

                                                                                                                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                  Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                                                                  Anticoagulant Factor Concentrate Treatment Trials

                                                                                                                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                  Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                                                                  Markers of Thrombin amp Plasmin Generation in DIC

                                                                                                                  D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                                                                  Cut-off value

                                                                                                                  Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                                                                  degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                                                                  D-dimer FDPs and DIC

                                                                                                                  D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                                                                  Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                                                                  Follow Up of DIC State of Disease

                                                                                                                  Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                                                                  Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                                                                  FMD-Dimer in DIC Major Differences

                                                                                                                  onset of thrombosis

                                                                                                                  days

                                                                                                                  Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                                                                  FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                                                                  D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                                                                  of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                                                                  0

                                                                                                                  20

                                                                                                                  40

                                                                                                                  60

                                                                                                                  80

                                                                                                                  100

                                                                                                                  94 85 90N = 62

                                                                                                                  Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                                                                  Positivity of Test Results ISTH Score and Disease State

                                                                                                                  Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                  Red bar positive for 2 points of DIC score

                                                                                                                  Pink bar positive for 1-2 points of DIC score

                                                                                                                  HT hematopoietic tumor

                                                                                                                  IF infection

                                                                                                                  SC solid cancer

                                                                                                                  Markers in Patients with or without DIC

                                                                                                                  Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                  HT hematopoietic tumorIF infectionSC solid cancer

                                                                                                                  Comparing an Automated FM vs Manual FSP Test

                                                                                                                  Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                                                  Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                                                  Automated (Mitsubishi) vs Automated (Stago)

                                                                                                                  In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                                                  Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                  In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                  In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                  In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                  Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                  No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                                  Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                  Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                  Non Overt DIC Overt DIC

                                                                                                                  AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                                  Trends in Markers of DIC for Different Patients

                                                                                                                  Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                                  Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                                  Trends in Markers of DIC for Different Patients

                                                                                                                  Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                  FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                                  28 day outcome survival

                                                                                                                  28 day outcome death

                                                                                                                  Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                  Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                  Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                                  Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                  Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                  Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                                  DIC Case Studies

                                                                                                                  Case Study 1 - Presentation

                                                                                                                  18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                  Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                  WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                  RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                  Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                  Hematocrit 195 401 ndash 510

                                                                                                                  MCV 95 fL 790 ndash 922 fL

                                                                                                                  MPV 12 fL 94 ndash 124 fL

                                                                                                                  Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                  Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                  Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                  PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                  APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                  Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                  D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                  Case Study 1 ndash Microscopy

                                                                                                                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                  Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                  Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                  DIC due to TF release by APL blasts

                                                                                                                  Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                  Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                  20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                  Case Study 2 ndash Presentation

                                                                                                                  TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                  PT 30 sec 113 ndash 146 sec

                                                                                                                  APTT 75 sec 25 ndash 34 sec

                                                                                                                  D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                  Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                  pH 728 738 to 742

                                                                                                                  PaO2 570 mmHg 80-100 mmHg

                                                                                                                  WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                  ALT 111 IUL 0ndash34 IUL

                                                                                                                  AST 61 IUL 0ndash34 IUL

                                                                                                                  BUN 303 mgdL 08-13 mgdL

                                                                                                                  Case Study 2 ndash Lab Results

                                                                                                                  Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                  Case Study 2 ndash Diagnosis

                                                                                                                  60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                  Case Study 3 ndash Presentation

                                                                                                                  TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                  PT 228 sec 113 ndash 146 sec

                                                                                                                  APTT 45 sec 25 ndash 34 sec

                                                                                                                  D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                  Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                  FV Normal 70-120

                                                                                                                  FVII Normal 55-170

                                                                                                                  FVIII Normal 60-150

                                                                                                                  Protein C Normal 70-130

                                                                                                                  Hb 134 gdL 14-16 gdL

                                                                                                                  WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                  ALT 32 IUL 0ndash34 IUL

                                                                                                                  AST 28 IUL 0ndash34 IUL

                                                                                                                  BUN 09 mgdL 08-13 mgdL

                                                                                                                  Case Study 3 ndash Lab Results

                                                                                                                  Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                  Case Study 3 ndash Diagnosis and Therapy

                                                                                                                  Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                  Case Study 4 ndash Presentation

                                                                                                                  TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                  PT 28 sec 113 ndash 146 sec

                                                                                                                  APTT 71 sec 25 ndash 34 sec

                                                                                                                  D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                  Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                  FV Normal 70-120

                                                                                                                  FVII Normal 55-170

                                                                                                                  FVIII Normal 60-150

                                                                                                                  Protein C Normal 70-130

                                                                                                                  Hb 158 gdL 14-16 gdL

                                                                                                                  WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                  ALT 60 IUL 0ndash34 IUL

                                                                                                                  AST 47 IUL 0ndash34 IUL

                                                                                                                  BUN 38 mgdL 08-13 mgdL

                                                                                                                  Case Study 4 ndash Lab Results

                                                                                                                  Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                  Case Study 4 ndash Diagnosis

                                                                                                                  55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                  Case Study 5 ndash Presentation

                                                                                                                  Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                  Case Study 5 ndash Lab Results and Time Course

                                                                                                                  Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                  TEST RESULT REFERENCE RANGE

                                                                                                                  Platelet count 33 x 109L 150-450 x 109L

                                                                                                                  PT 215 sec 103 ndash 128 sec

                                                                                                                  APTT 44 sec 26 ndash 36 sec

                                                                                                                  D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                  Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                  FII FV FVIII Low Not reported (NR)

                                                                                                                  FVII FIX FX vWF Normal NR

                                                                                                                  Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                  DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                  dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                  (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                  (D) Illustration demonstrating repair

                                                                                                                  Case Study 5 ndash Diagnosis and Treatment

                                                                                                                  Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                  29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                  Case Study 6 ndash Presentation

                                                                                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                  Case Study 6 ndash Lab Results

                                                                                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                  TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                  PT 63 sec gt control 113 ndash 146 sec

                                                                                                                  INR 658 1 ndash 125

                                                                                                                  APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                  D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                  Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                  Albumin 28 gdL NR

                                                                                                                  Hb 58 gdL NR

                                                                                                                  LDH 1196 UL NR

                                                                                                                  SGPT 144 IU NR

                                                                                                                  SGOT 88 IU NR

                                                                                                                  Bilirubin 32 mgdL NR

                                                                                                                  DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                  day postop

                                                                                                                  Case Study 6 ndash Diagnosis and Treatment

                                                                                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                  HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                  Case Study 6 ndash Discussion

                                                                                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                  44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                  Case Study 7 ndash Presentation

                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                  On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                  Case Study 7 ndash Presentation

                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                  Case Study 7 ndash Lab Results vs Time

                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                  Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                  Case Study 7 ndash Diagnosis and Treatment

                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                  On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                  Case Study 7 ndash Diagnosis and Treatment

                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                  DIC Take Home Messages

                                                                                                                  Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                  Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                  DIC

                                                                                                                  Thank you Questions

                                                                                                                  • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                  • Learning Objectives
                                                                                                                  • Slide Number 3
                                                                                                                  • Slide Number 4
                                                                                                                  • Slide Number 5
                                                                                                                  • Slide Number 6
                                                                                                                  • Slide Number 7
                                                                                                                  • Slide Number 8
                                                                                                                  • Wound Sealing
                                                                                                                  • The Three Steps of Hemostasis
                                                                                                                  • Vessel Wall
                                                                                                                  • Slide Number 12
                                                                                                                  • Slide Number 13
                                                                                                                  • Platelet Structure UnactivatedActivated
                                                                                                                  • Primary Hemostasis
                                                                                                                  • Primary Hemostasis Assays
                                                                                                                  • Slide Number 17
                                                                                                                  • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                  • Slide Number 19
                                                                                                                  • Coagulation factors
                                                                                                                  • Coagulation Assay Mechanisms
                                                                                                                  • Slide Number 22
                                                                                                                  • Fibrin Formation
                                                                                                                  • Slide Number 24
                                                                                                                  • Fibrinolysis Overview
                                                                                                                  • Fibrinolysis Overview
                                                                                                                  • Slide Number 27
                                                                                                                  • Fibrinolysis Releases D-dimers
                                                                                                                  • Basic Pathophysiology of DIC
                                                                                                                  • Disseminated Intravascular Coagulation (DIC)
                                                                                                                  • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                  • Clinical Conditions Associated With DIC
                                                                                                                  • Frequency of DIC in Selected Disease States
                                                                                                                  • Underlying Diseases in DIC Patients
                                                                                                                  • Slide Number 36
                                                                                                                  • Slide Number 37
                                                                                                                  • Slide Number 38
                                                                                                                  • Slide Number 39
                                                                                                                  • Pathophysiology of DIC
                                                                                                                  • Pathogenesis of DIC in Sepsis
                                                                                                                  • Host Response in Severe Sepsis
                                                                                                                  • Organ Failure in Severe Sepsis
                                                                                                                  • Mechanism of DIC in Organ Failure
                                                                                                                  • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                  • Slide Number 47
                                                                                                                  • Diverse and Opposing Effects of Thrombin
                                                                                                                  • Coagulation and Fibrinolysis in DIC
                                                                                                                  • Mechanism of DIC
                                                                                                                  • Pathophysiology of DIC
                                                                                                                  • Pathophysiology of DIC - Mechanism
                                                                                                                  • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                  • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                  • Pathophysiology of Overt DIC
                                                                                                                  • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                  • Slide Number 57
                                                                                                                  • Slide Number 58
                                                                                                                  • Slide Number 59
                                                                                                                  • Slide Number 60
                                                                                                                  • Slide Number 61
                                                                                                                  • BREAK
                                                                                                                  • Diagnostic and Management Approach for DIC
                                                                                                                  • Diagnosis of DIC
                                                                                                                  • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                  • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                  • Slide Number 67
                                                                                                                  • Slide Number 68
                                                                                                                  • British Journal of Haematology Overt DIC Score
                                                                                                                  • Slide Number 70
                                                                                                                  • Slide Number 71
                                                                                                                  • Slide Number 72
                                                                                                                  • Slide Number 73
                                                                                                                  • DIC Management Goals
                                                                                                                  • DIC Management and Treatment
                                                                                                                  • DIC Management Strategies
                                                                                                                  • Anticoagulant Factor Concentrate Treatment
                                                                                                                  • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                  • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                  • D-dimer FDPs and DIC
                                                                                                                  • D-Dimer and FDPs in DIC
                                                                                                                  • Follow Up of DIC State of Disease
                                                                                                                  • FMD-Dimer in DIC Major Differences
                                                                                                                  • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                  • Slide Number 85
                                                                                                                  • Slide Number 86
                                                                                                                  • Comparing an Automated FM vs Manual FSP Test
                                                                                                                  • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                  • Slide Number 94
                                                                                                                  • Slide Number 95
                                                                                                                  • Slide Number 96
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                                                                                                                  • DIC Case Studies
                                                                                                                  • Case Study 1 - Presentation
                                                                                                                  • Case Study 1 ndash Lab Results
                                                                                                                  • Case Study 1 ndash Microscopy
                                                                                                                  • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                  • Slide Number 105
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                                                                                                                  • DIC Take Home Messages
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                                                                                                                    Inflammation

                                                                                                                    Coagulation

                                                                                                                    Stago Celebrates Lab Week 2017

                                                                                                                    NA

                                                                                                                    Stago 247 Educational Webinar Sites

                                                                                                                    wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                                                                                                                    wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                                                                                                                    Stago Educational Apps

                                                                                                                    HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                                                                                                                    iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                                                                                                                    BREAK

                                                                                                                    Diagnostic and Management Approach for DIC

                                                                                                                    Diagnosis of DIC

                                                                                                                    Clinical diagnosis is obvious in cases of overt DIC

                                                                                                                    Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                                                                                                    Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                                                                                                    Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                                                                                                    Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                                                                                                    Important to recognize simultaneous formation of thrombin and plasmin

                                                                                                                    Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                                                    Lab Diagnosis of DIC ndash Screening Tests

                                                                                                                    Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                                                    Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                                                                                                    fibrinogen level) repeat testing assesses progression

                                                                                                                    Screening tests not clinically specific or sensitive for DIC

                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                    Laboratory Changes in Overt DIC

                                                                                                                    DIC Diagnostic Practices Over Time

                                                                                                                    Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                    British Journal of Haematology Overt DIC Score

                                                                                                                    Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                    ISTH Step by Step DIC Algorithm

                                                                                                                    Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                                                                                    US Based Validation of ISTH DIC Score

                                                                                                                    When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                    Differential Diagnosis in DIC

                                                                                                                    aHUS atypical hemolytic uremic syndrome

                                                                                                                    HUS hemolytic uremic syndrome

                                                                                                                    HIT heparin-induced thrombocytopenia

                                                                                                                    ITP immune thrombocytopenic purpura

                                                                                                                    TTP thrombotic thrombocytopenic purpura

                                                                                                                    DIC and MAHA

                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                    lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                                                                                    When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                                                                                    DIC Management Goals

                                                                                                                    Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                                    Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                                                                                    DIC Management and Treatment

                                                                                                                    Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                                    Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                                                                                    requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                                                                                    Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                                                                                    DIC Management Strategies

                                                                                                                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                    Anticoagulant Factor Concentrate Treatment

                                                                                                                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                    Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                                                                    Anticoagulant Factor Concentrate Treatment Trials

                                                                                                                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                    Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                                                                    Markers of Thrombin amp Plasmin Generation in DIC

                                                                                                                    D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                                                                    Cut-off value

                                                                                                                    Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                                                                    degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                                                                    D-dimer FDPs and DIC

                                                                                                                    D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                                                                    Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                                                                    Follow Up of DIC State of Disease

                                                                                                                    Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                                                                    Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                                                                    FMD-Dimer in DIC Major Differences

                                                                                                                    onset of thrombosis

                                                                                                                    days

                                                                                                                    Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                                                                    FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                                                                    D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                                                                    of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                                                                    0

                                                                                                                    20

                                                                                                                    40

                                                                                                                    60

                                                                                                                    80

                                                                                                                    100

                                                                                                                    94 85 90N = 62

                                                                                                                    Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                                                                    Positivity of Test Results ISTH Score and Disease State

                                                                                                                    Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                    Red bar positive for 2 points of DIC score

                                                                                                                    Pink bar positive for 1-2 points of DIC score

                                                                                                                    HT hematopoietic tumor

                                                                                                                    IF infection

                                                                                                                    SC solid cancer

                                                                                                                    Markers in Patients with or without DIC

                                                                                                                    Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                    HT hematopoietic tumorIF infectionSC solid cancer

                                                                                                                    Comparing an Automated FM vs Manual FSP Test

                                                                                                                    Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                                                    Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                                                    Automated (Mitsubishi) vs Automated (Stago)

                                                                                                                    In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                                                    Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                    In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                    In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                    In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                    Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                    No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                                    Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                    Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                    Non Overt DIC Overt DIC

                                                                                                                    AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                                    Trends in Markers of DIC for Different Patients

                                                                                                                    Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                                    Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                                    Trends in Markers of DIC for Different Patients

                                                                                                                    Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                    FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                                    28 day outcome survival

                                                                                                                    28 day outcome death

                                                                                                                    Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                    Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                    Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                                    Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                    Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                    Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                                    DIC Case Studies

                                                                                                                    Case Study 1 - Presentation

                                                                                                                    18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                    Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                    WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                    RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                    Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                    Hematocrit 195 401 ndash 510

                                                                                                                    MCV 95 fL 790 ndash 922 fL

                                                                                                                    MPV 12 fL 94 ndash 124 fL

                                                                                                                    Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                    Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                    Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                    PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                    APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                    Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                    D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                    Case Study 1 ndash Microscopy

                                                                                                                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                    Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                    Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                    DIC due to TF release by APL blasts

                                                                                                                    Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                    Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                    20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                    Case Study 2 ndash Presentation

                                                                                                                    TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                    PT 30 sec 113 ndash 146 sec

                                                                                                                    APTT 75 sec 25 ndash 34 sec

                                                                                                                    D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                    Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                    pH 728 738 to 742

                                                                                                                    PaO2 570 mmHg 80-100 mmHg

                                                                                                                    WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                    ALT 111 IUL 0ndash34 IUL

                                                                                                                    AST 61 IUL 0ndash34 IUL

                                                                                                                    BUN 303 mgdL 08-13 mgdL

                                                                                                                    Case Study 2 ndash Lab Results

                                                                                                                    Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                    Case Study 2 ndash Diagnosis

                                                                                                                    60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                    Case Study 3 ndash Presentation

                                                                                                                    TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                    PT 228 sec 113 ndash 146 sec

                                                                                                                    APTT 45 sec 25 ndash 34 sec

                                                                                                                    D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                    Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                    FV Normal 70-120

                                                                                                                    FVII Normal 55-170

                                                                                                                    FVIII Normal 60-150

                                                                                                                    Protein C Normal 70-130

                                                                                                                    Hb 134 gdL 14-16 gdL

                                                                                                                    WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                    ALT 32 IUL 0ndash34 IUL

                                                                                                                    AST 28 IUL 0ndash34 IUL

                                                                                                                    BUN 09 mgdL 08-13 mgdL

                                                                                                                    Case Study 3 ndash Lab Results

                                                                                                                    Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                    Case Study 3 ndash Diagnosis and Therapy

                                                                                                                    Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                    Case Study 4 ndash Presentation

                                                                                                                    TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                    PT 28 sec 113 ndash 146 sec

                                                                                                                    APTT 71 sec 25 ndash 34 sec

                                                                                                                    D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                    Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                    FV Normal 70-120

                                                                                                                    FVII Normal 55-170

                                                                                                                    FVIII Normal 60-150

                                                                                                                    Protein C Normal 70-130

                                                                                                                    Hb 158 gdL 14-16 gdL

                                                                                                                    WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                    ALT 60 IUL 0ndash34 IUL

                                                                                                                    AST 47 IUL 0ndash34 IUL

                                                                                                                    BUN 38 mgdL 08-13 mgdL

                                                                                                                    Case Study 4 ndash Lab Results

                                                                                                                    Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                    Case Study 4 ndash Diagnosis

                                                                                                                    55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                    Case Study 5 ndash Presentation

                                                                                                                    Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                    Case Study 5 ndash Lab Results and Time Course

                                                                                                                    Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                    TEST RESULT REFERENCE RANGE

                                                                                                                    Platelet count 33 x 109L 150-450 x 109L

                                                                                                                    PT 215 sec 103 ndash 128 sec

                                                                                                                    APTT 44 sec 26 ndash 36 sec

                                                                                                                    D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                    Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                    FII FV FVIII Low Not reported (NR)

                                                                                                                    FVII FIX FX vWF Normal NR

                                                                                                                    Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                    DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                    dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                    (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                    (D) Illustration demonstrating repair

                                                                                                                    Case Study 5 ndash Diagnosis and Treatment

                                                                                                                    Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                    29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                    Case Study 6 ndash Presentation

                                                                                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                    Case Study 6 ndash Lab Results

                                                                                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                    TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                    PT 63 sec gt control 113 ndash 146 sec

                                                                                                                    INR 658 1 ndash 125

                                                                                                                    APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                    D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                    Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                    Albumin 28 gdL NR

                                                                                                                    Hb 58 gdL NR

                                                                                                                    LDH 1196 UL NR

                                                                                                                    SGPT 144 IU NR

                                                                                                                    SGOT 88 IU NR

                                                                                                                    Bilirubin 32 mgdL NR

                                                                                                                    DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                    day postop

                                                                                                                    Case Study 6 ndash Diagnosis and Treatment

                                                                                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                    HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                    Case Study 6 ndash Discussion

                                                                                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                    44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                    Case Study 7 ndash Presentation

                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                    On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                    Case Study 7 ndash Presentation

                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                    Case Study 7 ndash Lab Results vs Time

                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                    Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                    Case Study 7 ndash Diagnosis and Treatment

                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                    On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                    Case Study 7 ndash Diagnosis and Treatment

                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                    DIC Take Home Messages

                                                                                                                    Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                    Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                    DIC

                                                                                                                    Thank you Questions

                                                                                                                    • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                    • Learning Objectives
                                                                                                                    • Slide Number 3
                                                                                                                    • Slide Number 4
                                                                                                                    • Slide Number 5
                                                                                                                    • Slide Number 6
                                                                                                                    • Slide Number 7
                                                                                                                    • Slide Number 8
                                                                                                                    • Wound Sealing
                                                                                                                    • The Three Steps of Hemostasis
                                                                                                                    • Vessel Wall
                                                                                                                    • Slide Number 12
                                                                                                                    • Slide Number 13
                                                                                                                    • Platelet Structure UnactivatedActivated
                                                                                                                    • Primary Hemostasis
                                                                                                                    • Primary Hemostasis Assays
                                                                                                                    • Slide Number 17
                                                                                                                    • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                    • Slide Number 19
                                                                                                                    • Coagulation factors
                                                                                                                    • Coagulation Assay Mechanisms
                                                                                                                    • Slide Number 22
                                                                                                                    • Fibrin Formation
                                                                                                                    • Slide Number 24
                                                                                                                    • Fibrinolysis Overview
                                                                                                                    • Fibrinolysis Overview
                                                                                                                    • Slide Number 27
                                                                                                                    • Fibrinolysis Releases D-dimers
                                                                                                                    • Basic Pathophysiology of DIC
                                                                                                                    • Disseminated Intravascular Coagulation (DIC)
                                                                                                                    • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                    • Clinical Conditions Associated With DIC
                                                                                                                    • Frequency of DIC in Selected Disease States
                                                                                                                    • Underlying Diseases in DIC Patients
                                                                                                                    • Slide Number 36
                                                                                                                    • Slide Number 37
                                                                                                                    • Slide Number 38
                                                                                                                    • Slide Number 39
                                                                                                                    • Pathophysiology of DIC
                                                                                                                    • Pathogenesis of DIC in Sepsis
                                                                                                                    • Host Response in Severe Sepsis
                                                                                                                    • Organ Failure in Severe Sepsis
                                                                                                                    • Mechanism of DIC in Organ Failure
                                                                                                                    • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                    • Slide Number 47
                                                                                                                    • Diverse and Opposing Effects of Thrombin
                                                                                                                    • Coagulation and Fibrinolysis in DIC
                                                                                                                    • Mechanism of DIC
                                                                                                                    • Pathophysiology of DIC
                                                                                                                    • Pathophysiology of DIC - Mechanism
                                                                                                                    • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                    • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                    • Pathophysiology of Overt DIC
                                                                                                                    • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                    • Slide Number 57
                                                                                                                    • Slide Number 58
                                                                                                                    • Slide Number 59
                                                                                                                    • Slide Number 60
                                                                                                                    • Slide Number 61
                                                                                                                    • BREAK
                                                                                                                    • Diagnostic and Management Approach for DIC
                                                                                                                    • Diagnosis of DIC
                                                                                                                    • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                    • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                    • Slide Number 67
                                                                                                                    • Slide Number 68
                                                                                                                    • British Journal of Haematology Overt DIC Score
                                                                                                                    • Slide Number 70
                                                                                                                    • Slide Number 71
                                                                                                                    • Slide Number 72
                                                                                                                    • Slide Number 73
                                                                                                                    • DIC Management Goals
                                                                                                                    • DIC Management and Treatment
                                                                                                                    • DIC Management Strategies
                                                                                                                    • Anticoagulant Factor Concentrate Treatment
                                                                                                                    • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                    • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                    • D-dimer FDPs and DIC
                                                                                                                    • D-Dimer and FDPs in DIC
                                                                                                                    • Follow Up of DIC State of Disease
                                                                                                                    • FMD-Dimer in DIC Major Differences
                                                                                                                    • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                    • Slide Number 85
                                                                                                                    • Slide Number 86
                                                                                                                    • Comparing an Automated FM vs Manual FSP Test
                                                                                                                    • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                    • Slide Number 94
                                                                                                                    • Slide Number 95
                                                                                                                    • Slide Number 96
                                                                                                                    • Slide Number 97
                                                                                                                    • Slide Number 98
                                                                                                                    • Slide Number 99
                                                                                                                    • DIC Case Studies
                                                                                                                    • Case Study 1 - Presentation
                                                                                                                    • Case Study 1 ndash Lab Results
                                                                                                                    • Case Study 1 ndash Microscopy
                                                                                                                    • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                    • Slide Number 105
                                                                                                                    • Slide Number 106
                                                                                                                    • Slide Number 107
                                                                                                                    • Slide Number 108
                                                                                                                    • Slide Number 109
                                                                                                                    • Slide Number 110
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                                                                                                                    • Slide Number 122
                                                                                                                    • Slide Number 123
                                                                                                                    • Slide Number 124
                                                                                                                    • Slide Number 125
                                                                                                                    • DIC Take Home Messages
                                                                                                                    • Slide Number 127
                                                                                                                    • Slide Number 128

                                                                                                                      Stago Celebrates Lab Week 2017

                                                                                                                      NA

                                                                                                                      Stago 247 Educational Webinar Sites

                                                                                                                      wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                                                                                                                      wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                                                                                                                      Stago Educational Apps

                                                                                                                      HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                                                                                                                      iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                                                                                                                      BREAK

                                                                                                                      Diagnostic and Management Approach for DIC

                                                                                                                      Diagnosis of DIC

                                                                                                                      Clinical diagnosis is obvious in cases of overt DIC

                                                                                                                      Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                                                                                                      Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                                                                                                      Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                                                                                                      Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                                                                                                      Important to recognize simultaneous formation of thrombin and plasmin

                                                                                                                      Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                                                      Lab Diagnosis of DIC ndash Screening Tests

                                                                                                                      Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                                                      Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                                                                                                      fibrinogen level) repeat testing assesses progression

                                                                                                                      Screening tests not clinically specific or sensitive for DIC

                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                      Laboratory Changes in Overt DIC

                                                                                                                      DIC Diagnostic Practices Over Time

                                                                                                                      Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                      British Journal of Haematology Overt DIC Score

                                                                                                                      Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                      ISTH Step by Step DIC Algorithm

                                                                                                                      Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                                                                                      US Based Validation of ISTH DIC Score

                                                                                                                      When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                      Differential Diagnosis in DIC

                                                                                                                      aHUS atypical hemolytic uremic syndrome

                                                                                                                      HUS hemolytic uremic syndrome

                                                                                                                      HIT heparin-induced thrombocytopenia

                                                                                                                      ITP immune thrombocytopenic purpura

                                                                                                                      TTP thrombotic thrombocytopenic purpura

                                                                                                                      DIC and MAHA

                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                      lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                                                                                      When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                                                                                      DIC Management Goals

                                                                                                                      Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                                      Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                                                                                      DIC Management and Treatment

                                                                                                                      Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                                      Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                                                                                      requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                                                                                      Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                                                                                      DIC Management Strategies

                                                                                                                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                      Anticoagulant Factor Concentrate Treatment

                                                                                                                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                      Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                                                                      Anticoagulant Factor Concentrate Treatment Trials

                                                                                                                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                      Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                                                                      Markers of Thrombin amp Plasmin Generation in DIC

                                                                                                                      D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                                                                      Cut-off value

                                                                                                                      Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                                                                      degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                                                                      D-dimer FDPs and DIC

                                                                                                                      D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                                                                      Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                                                                      Follow Up of DIC State of Disease

                                                                                                                      Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                                                                      Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                                                                      FMD-Dimer in DIC Major Differences

                                                                                                                      onset of thrombosis

                                                                                                                      days

                                                                                                                      Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                                                                      FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                                                                      D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                                                                      of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                                                                      0

                                                                                                                      20

                                                                                                                      40

                                                                                                                      60

                                                                                                                      80

                                                                                                                      100

                                                                                                                      94 85 90N = 62

                                                                                                                      Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                                                                      Positivity of Test Results ISTH Score and Disease State

                                                                                                                      Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                      Red bar positive for 2 points of DIC score

                                                                                                                      Pink bar positive for 1-2 points of DIC score

                                                                                                                      HT hematopoietic tumor

                                                                                                                      IF infection

                                                                                                                      SC solid cancer

                                                                                                                      Markers in Patients with or without DIC

                                                                                                                      Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                      HT hematopoietic tumorIF infectionSC solid cancer

                                                                                                                      Comparing an Automated FM vs Manual FSP Test

                                                                                                                      Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                                                      Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                                                      Automated (Mitsubishi) vs Automated (Stago)

                                                                                                                      In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                                                      Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                      In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                      In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                      In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                      Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                      No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                                      Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                      Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                      Non Overt DIC Overt DIC

                                                                                                                      AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                                      Trends in Markers of DIC for Different Patients

                                                                                                                      Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                                      Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                                      Trends in Markers of DIC for Different Patients

                                                                                                                      Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                      FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                                      28 day outcome survival

                                                                                                                      28 day outcome death

                                                                                                                      Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                      Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                      Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                                      Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                      Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                      Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                                      DIC Case Studies

                                                                                                                      Case Study 1 - Presentation

                                                                                                                      18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                      Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                      WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                      RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                      Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                      Hematocrit 195 401 ndash 510

                                                                                                                      MCV 95 fL 790 ndash 922 fL

                                                                                                                      MPV 12 fL 94 ndash 124 fL

                                                                                                                      Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                      Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                      Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                      PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                      APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                      Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                      D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                      Case Study 1 ndash Microscopy

                                                                                                                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                      Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                      Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                      DIC due to TF release by APL blasts

                                                                                                                      Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                      Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                      20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                      Case Study 2 ndash Presentation

                                                                                                                      TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                      PT 30 sec 113 ndash 146 sec

                                                                                                                      APTT 75 sec 25 ndash 34 sec

                                                                                                                      D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                      Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                      pH 728 738 to 742

                                                                                                                      PaO2 570 mmHg 80-100 mmHg

                                                                                                                      WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                      ALT 111 IUL 0ndash34 IUL

                                                                                                                      AST 61 IUL 0ndash34 IUL

                                                                                                                      BUN 303 mgdL 08-13 mgdL

                                                                                                                      Case Study 2 ndash Lab Results

                                                                                                                      Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                      Case Study 2 ndash Diagnosis

                                                                                                                      60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                      Case Study 3 ndash Presentation

                                                                                                                      TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                      PT 228 sec 113 ndash 146 sec

                                                                                                                      APTT 45 sec 25 ndash 34 sec

                                                                                                                      D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                      Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                      FV Normal 70-120

                                                                                                                      FVII Normal 55-170

                                                                                                                      FVIII Normal 60-150

                                                                                                                      Protein C Normal 70-130

                                                                                                                      Hb 134 gdL 14-16 gdL

                                                                                                                      WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                      ALT 32 IUL 0ndash34 IUL

                                                                                                                      AST 28 IUL 0ndash34 IUL

                                                                                                                      BUN 09 mgdL 08-13 mgdL

                                                                                                                      Case Study 3 ndash Lab Results

                                                                                                                      Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                      Case Study 3 ndash Diagnosis and Therapy

                                                                                                                      Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                      Case Study 4 ndash Presentation

                                                                                                                      TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                      PT 28 sec 113 ndash 146 sec

                                                                                                                      APTT 71 sec 25 ndash 34 sec

                                                                                                                      D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                      Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                      FV Normal 70-120

                                                                                                                      FVII Normal 55-170

                                                                                                                      FVIII Normal 60-150

                                                                                                                      Protein C Normal 70-130

                                                                                                                      Hb 158 gdL 14-16 gdL

                                                                                                                      WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                      ALT 60 IUL 0ndash34 IUL

                                                                                                                      AST 47 IUL 0ndash34 IUL

                                                                                                                      BUN 38 mgdL 08-13 mgdL

                                                                                                                      Case Study 4 ndash Lab Results

                                                                                                                      Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                      Case Study 4 ndash Diagnosis

                                                                                                                      55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                      Case Study 5 ndash Presentation

                                                                                                                      Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                      Case Study 5 ndash Lab Results and Time Course

                                                                                                                      Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                      TEST RESULT REFERENCE RANGE

                                                                                                                      Platelet count 33 x 109L 150-450 x 109L

                                                                                                                      PT 215 sec 103 ndash 128 sec

                                                                                                                      APTT 44 sec 26 ndash 36 sec

                                                                                                                      D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                      Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                      FII FV FVIII Low Not reported (NR)

                                                                                                                      FVII FIX FX vWF Normal NR

                                                                                                                      Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                      DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                      dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                      (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                      (D) Illustration demonstrating repair

                                                                                                                      Case Study 5 ndash Diagnosis and Treatment

                                                                                                                      Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                      29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                      Case Study 6 ndash Presentation

                                                                                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                      Case Study 6 ndash Lab Results

                                                                                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                      TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                      PT 63 sec gt control 113 ndash 146 sec

                                                                                                                      INR 658 1 ndash 125

                                                                                                                      APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                      D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                      Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                      Albumin 28 gdL NR

                                                                                                                      Hb 58 gdL NR

                                                                                                                      LDH 1196 UL NR

                                                                                                                      SGPT 144 IU NR

                                                                                                                      SGOT 88 IU NR

                                                                                                                      Bilirubin 32 mgdL NR

                                                                                                                      DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                      day postop

                                                                                                                      Case Study 6 ndash Diagnosis and Treatment

                                                                                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                      HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                      Case Study 6 ndash Discussion

                                                                                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                      44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                      Case Study 7 ndash Presentation

                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                      On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                      Case Study 7 ndash Presentation

                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                      Case Study 7 ndash Lab Results vs Time

                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                      Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                      Case Study 7 ndash Diagnosis and Treatment

                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                      On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                      Case Study 7 ndash Diagnosis and Treatment

                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                      DIC Take Home Messages

                                                                                                                      Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                      Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                      DIC

                                                                                                                      Thank you Questions

                                                                                                                      • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                      • Learning Objectives
                                                                                                                      • Slide Number 3
                                                                                                                      • Slide Number 4
                                                                                                                      • Slide Number 5
                                                                                                                      • Slide Number 6
                                                                                                                      • Slide Number 7
                                                                                                                      • Slide Number 8
                                                                                                                      • Wound Sealing
                                                                                                                      • The Three Steps of Hemostasis
                                                                                                                      • Vessel Wall
                                                                                                                      • Slide Number 12
                                                                                                                      • Slide Number 13
                                                                                                                      • Platelet Structure UnactivatedActivated
                                                                                                                      • Primary Hemostasis
                                                                                                                      • Primary Hemostasis Assays
                                                                                                                      • Slide Number 17
                                                                                                                      • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                      • Slide Number 19
                                                                                                                      • Coagulation factors
                                                                                                                      • Coagulation Assay Mechanisms
                                                                                                                      • Slide Number 22
                                                                                                                      • Fibrin Formation
                                                                                                                      • Slide Number 24
                                                                                                                      • Fibrinolysis Overview
                                                                                                                      • Fibrinolysis Overview
                                                                                                                      • Slide Number 27
                                                                                                                      • Fibrinolysis Releases D-dimers
                                                                                                                      • Basic Pathophysiology of DIC
                                                                                                                      • Disseminated Intravascular Coagulation (DIC)
                                                                                                                      • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                      • Clinical Conditions Associated With DIC
                                                                                                                      • Frequency of DIC in Selected Disease States
                                                                                                                      • Underlying Diseases in DIC Patients
                                                                                                                      • Slide Number 36
                                                                                                                      • Slide Number 37
                                                                                                                      • Slide Number 38
                                                                                                                      • Slide Number 39
                                                                                                                      • Pathophysiology of DIC
                                                                                                                      • Pathogenesis of DIC in Sepsis
                                                                                                                      • Host Response in Severe Sepsis
                                                                                                                      • Organ Failure in Severe Sepsis
                                                                                                                      • Mechanism of DIC in Organ Failure
                                                                                                                      • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                      • Slide Number 47
                                                                                                                      • Diverse and Opposing Effects of Thrombin
                                                                                                                      • Coagulation and Fibrinolysis in DIC
                                                                                                                      • Mechanism of DIC
                                                                                                                      • Pathophysiology of DIC
                                                                                                                      • Pathophysiology of DIC - Mechanism
                                                                                                                      • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                      • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                      • Pathophysiology of Overt DIC
                                                                                                                      • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                      • Slide Number 57
                                                                                                                      • Slide Number 58
                                                                                                                      • Slide Number 59
                                                                                                                      • Slide Number 60
                                                                                                                      • Slide Number 61
                                                                                                                      • BREAK
                                                                                                                      • Diagnostic and Management Approach for DIC
                                                                                                                      • Diagnosis of DIC
                                                                                                                      • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                      • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                      • Slide Number 67
                                                                                                                      • Slide Number 68
                                                                                                                      • British Journal of Haematology Overt DIC Score
                                                                                                                      • Slide Number 70
                                                                                                                      • Slide Number 71
                                                                                                                      • Slide Number 72
                                                                                                                      • Slide Number 73
                                                                                                                      • DIC Management Goals
                                                                                                                      • DIC Management and Treatment
                                                                                                                      • DIC Management Strategies
                                                                                                                      • Anticoagulant Factor Concentrate Treatment
                                                                                                                      • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                      • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                      • D-dimer FDPs and DIC
                                                                                                                      • D-Dimer and FDPs in DIC
                                                                                                                      • Follow Up of DIC State of Disease
                                                                                                                      • FMD-Dimer in DIC Major Differences
                                                                                                                      • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                      • Slide Number 85
                                                                                                                      • Slide Number 86
                                                                                                                      • Comparing an Automated FM vs Manual FSP Test
                                                                                                                      • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                      • Slide Number 94
                                                                                                                      • Slide Number 95
                                                                                                                      • Slide Number 96
                                                                                                                      • Slide Number 97
                                                                                                                      • Slide Number 98
                                                                                                                      • Slide Number 99
                                                                                                                      • DIC Case Studies
                                                                                                                      • Case Study 1 - Presentation
                                                                                                                      • Case Study 1 ndash Lab Results
                                                                                                                      • Case Study 1 ndash Microscopy
                                                                                                                      • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                      • Slide Number 105
                                                                                                                      • Slide Number 106
                                                                                                                      • Slide Number 107
                                                                                                                      • Slide Number 108
                                                                                                                      • Slide Number 109
                                                                                                                      • Slide Number 110
                                                                                                                      • Slide Number 111
                                                                                                                      • Slide Number 112
                                                                                                                      • Slide Number 113
                                                                                                                      • Slide Number 114
                                                                                                                      • Slide Number 115
                                                                                                                      • Slide Number 116
                                                                                                                      • Slide Number 117
                                                                                                                      • Slide Number 118
                                                                                                                      • Slide Number 119
                                                                                                                      • Slide Number 120
                                                                                                                      • Slide Number 121
                                                                                                                      • Slide Number 122
                                                                                                                      • Slide Number 123
                                                                                                                      • Slide Number 124
                                                                                                                      • Slide Number 125
                                                                                                                      • DIC Take Home Messages
                                                                                                                      • Slide Number 127
                                                                                                                      • Slide Number 128

                                                                                                                        Stago 247 Educational Webinar Sites

                                                                                                                        wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall

                                                                                                                        wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion

                                                                                                                        Stago Educational Apps

                                                                                                                        HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                                                                                                                        iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                                                                                                                        BREAK

                                                                                                                        Diagnostic and Management Approach for DIC

                                                                                                                        Diagnosis of DIC

                                                                                                                        Clinical diagnosis is obvious in cases of overt DIC

                                                                                                                        Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                                                                                                        Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                                                                                                        Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                                                                                                        Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                                                                                                        Important to recognize simultaneous formation of thrombin and plasmin

                                                                                                                        Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                                                        Lab Diagnosis of DIC ndash Screening Tests

                                                                                                                        Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                                                        Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                                                                                                        fibrinogen level) repeat testing assesses progression

                                                                                                                        Screening tests not clinically specific or sensitive for DIC

                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                        Laboratory Changes in Overt DIC

                                                                                                                        DIC Diagnostic Practices Over Time

                                                                                                                        Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                        British Journal of Haematology Overt DIC Score

                                                                                                                        Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                        ISTH Step by Step DIC Algorithm

                                                                                                                        Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                                                                                        US Based Validation of ISTH DIC Score

                                                                                                                        When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                        Differential Diagnosis in DIC

                                                                                                                        aHUS atypical hemolytic uremic syndrome

                                                                                                                        HUS hemolytic uremic syndrome

                                                                                                                        HIT heparin-induced thrombocytopenia

                                                                                                                        ITP immune thrombocytopenic purpura

                                                                                                                        TTP thrombotic thrombocytopenic purpura

                                                                                                                        DIC and MAHA

                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                        lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                                                                                        When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                                                                                        DIC Management Goals

                                                                                                                        Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                                        Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                                                                                        DIC Management and Treatment

                                                                                                                        Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                                        Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                                                                                        requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                                                                                        Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                                                                                        DIC Management Strategies

                                                                                                                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                        Anticoagulant Factor Concentrate Treatment

                                                                                                                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                        Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                                                                        Anticoagulant Factor Concentrate Treatment Trials

                                                                                                                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                        Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                                                                        Markers of Thrombin amp Plasmin Generation in DIC

                                                                                                                        D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                                                                        Cut-off value

                                                                                                                        Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                                                                        degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                                                                        D-dimer FDPs and DIC

                                                                                                                        D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                                                                        Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                                                                        Follow Up of DIC State of Disease

                                                                                                                        Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                                                                        Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                                                                        FMD-Dimer in DIC Major Differences

                                                                                                                        onset of thrombosis

                                                                                                                        days

                                                                                                                        Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                                                                        FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                                                                        D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                                                                        of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                                                                        0

                                                                                                                        20

                                                                                                                        40

                                                                                                                        60

                                                                                                                        80

                                                                                                                        100

                                                                                                                        94 85 90N = 62

                                                                                                                        Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                                                                        Positivity of Test Results ISTH Score and Disease State

                                                                                                                        Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                        Red bar positive for 2 points of DIC score

                                                                                                                        Pink bar positive for 1-2 points of DIC score

                                                                                                                        HT hematopoietic tumor

                                                                                                                        IF infection

                                                                                                                        SC solid cancer

                                                                                                                        Markers in Patients with or without DIC

                                                                                                                        Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                        HT hematopoietic tumorIF infectionSC solid cancer

                                                                                                                        Comparing an Automated FM vs Manual FSP Test

                                                                                                                        Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                                                        Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                                                        Automated (Mitsubishi) vs Automated (Stago)

                                                                                                                        In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                                                        Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                        In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                        In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                        In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                        Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                        No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                                        Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                        Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                        Non Overt DIC Overt DIC

                                                                                                                        AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                                        Trends in Markers of DIC for Different Patients

                                                                                                                        Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                                        Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                                        Trends in Markers of DIC for Different Patients

                                                                                                                        Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                        FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                                        28 day outcome survival

                                                                                                                        28 day outcome death

                                                                                                                        Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                        Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                        Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                                        Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                        Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                        Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                                        DIC Case Studies

                                                                                                                        Case Study 1 - Presentation

                                                                                                                        18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                        Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                        WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                        RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                        Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                        Hematocrit 195 401 ndash 510

                                                                                                                        MCV 95 fL 790 ndash 922 fL

                                                                                                                        MPV 12 fL 94 ndash 124 fL

                                                                                                                        Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                        Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                        Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                        PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                        APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                        Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                        D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                        Case Study 1 ndash Microscopy

                                                                                                                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                        Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                        Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                        DIC due to TF release by APL blasts

                                                                                                                        Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                        Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                        20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                        Case Study 2 ndash Presentation

                                                                                                                        TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                        PT 30 sec 113 ndash 146 sec

                                                                                                                        APTT 75 sec 25 ndash 34 sec

                                                                                                                        D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                        Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                        pH 728 738 to 742

                                                                                                                        PaO2 570 mmHg 80-100 mmHg

                                                                                                                        WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                        ALT 111 IUL 0ndash34 IUL

                                                                                                                        AST 61 IUL 0ndash34 IUL

                                                                                                                        BUN 303 mgdL 08-13 mgdL

                                                                                                                        Case Study 2 ndash Lab Results

                                                                                                                        Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                        Case Study 2 ndash Diagnosis

                                                                                                                        60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                        Case Study 3 ndash Presentation

                                                                                                                        TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                        PT 228 sec 113 ndash 146 sec

                                                                                                                        APTT 45 sec 25 ndash 34 sec

                                                                                                                        D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                        Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                        FV Normal 70-120

                                                                                                                        FVII Normal 55-170

                                                                                                                        FVIII Normal 60-150

                                                                                                                        Protein C Normal 70-130

                                                                                                                        Hb 134 gdL 14-16 gdL

                                                                                                                        WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                        ALT 32 IUL 0ndash34 IUL

                                                                                                                        AST 28 IUL 0ndash34 IUL

                                                                                                                        BUN 09 mgdL 08-13 mgdL

                                                                                                                        Case Study 3 ndash Lab Results

                                                                                                                        Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                        Case Study 3 ndash Diagnosis and Therapy

                                                                                                                        Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                        Case Study 4 ndash Presentation

                                                                                                                        TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                        PT 28 sec 113 ndash 146 sec

                                                                                                                        APTT 71 sec 25 ndash 34 sec

                                                                                                                        D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                        Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                        FV Normal 70-120

                                                                                                                        FVII Normal 55-170

                                                                                                                        FVIII Normal 60-150

                                                                                                                        Protein C Normal 70-130

                                                                                                                        Hb 158 gdL 14-16 gdL

                                                                                                                        WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                        ALT 60 IUL 0ndash34 IUL

                                                                                                                        AST 47 IUL 0ndash34 IUL

                                                                                                                        BUN 38 mgdL 08-13 mgdL

                                                                                                                        Case Study 4 ndash Lab Results

                                                                                                                        Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                        Case Study 4 ndash Diagnosis

                                                                                                                        55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                        Case Study 5 ndash Presentation

                                                                                                                        Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                        Case Study 5 ndash Lab Results and Time Course

                                                                                                                        Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                        TEST RESULT REFERENCE RANGE

                                                                                                                        Platelet count 33 x 109L 150-450 x 109L

                                                                                                                        PT 215 sec 103 ndash 128 sec

                                                                                                                        APTT 44 sec 26 ndash 36 sec

                                                                                                                        D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                        Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                        FII FV FVIII Low Not reported (NR)

                                                                                                                        FVII FIX FX vWF Normal NR

                                                                                                                        Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                        DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                        dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                        (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                        (D) Illustration demonstrating repair

                                                                                                                        Case Study 5 ndash Diagnosis and Treatment

                                                                                                                        Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                        29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                        Case Study 6 ndash Presentation

                                                                                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                        Case Study 6 ndash Lab Results

                                                                                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                        TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                        PT 63 sec gt control 113 ndash 146 sec

                                                                                                                        INR 658 1 ndash 125

                                                                                                                        APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                        D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                        Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                        Albumin 28 gdL NR

                                                                                                                        Hb 58 gdL NR

                                                                                                                        LDH 1196 UL NR

                                                                                                                        SGPT 144 IU NR

                                                                                                                        SGOT 88 IU NR

                                                                                                                        Bilirubin 32 mgdL NR

                                                                                                                        DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                        day postop

                                                                                                                        Case Study 6 ndash Diagnosis and Treatment

                                                                                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                        HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                        Case Study 6 ndash Discussion

                                                                                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                        44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                        Case Study 7 ndash Presentation

                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                        On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                        Case Study 7 ndash Presentation

                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                        Case Study 7 ndash Lab Results vs Time

                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                        Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                        Case Study 7 ndash Diagnosis and Treatment

                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                        On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                        Case Study 7 ndash Diagnosis and Treatment

                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                        DIC Take Home Messages

                                                                                                                        Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                        Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                        DIC

                                                                                                                        Thank you Questions

                                                                                                                        • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                        • Learning Objectives
                                                                                                                        • Slide Number 3
                                                                                                                        • Slide Number 4
                                                                                                                        • Slide Number 5
                                                                                                                        • Slide Number 6
                                                                                                                        • Slide Number 7
                                                                                                                        • Slide Number 8
                                                                                                                        • Wound Sealing
                                                                                                                        • The Three Steps of Hemostasis
                                                                                                                        • Vessel Wall
                                                                                                                        • Slide Number 12
                                                                                                                        • Slide Number 13
                                                                                                                        • Platelet Structure UnactivatedActivated
                                                                                                                        • Primary Hemostasis
                                                                                                                        • Primary Hemostasis Assays
                                                                                                                        • Slide Number 17
                                                                                                                        • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                        • Slide Number 19
                                                                                                                        • Coagulation factors
                                                                                                                        • Coagulation Assay Mechanisms
                                                                                                                        • Slide Number 22
                                                                                                                        • Fibrin Formation
                                                                                                                        • Slide Number 24
                                                                                                                        • Fibrinolysis Overview
                                                                                                                        • Fibrinolysis Overview
                                                                                                                        • Slide Number 27
                                                                                                                        • Fibrinolysis Releases D-dimers
                                                                                                                        • Basic Pathophysiology of DIC
                                                                                                                        • Disseminated Intravascular Coagulation (DIC)
                                                                                                                        • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                        • Clinical Conditions Associated With DIC
                                                                                                                        • Frequency of DIC in Selected Disease States
                                                                                                                        • Underlying Diseases in DIC Patients
                                                                                                                        • Slide Number 36
                                                                                                                        • Slide Number 37
                                                                                                                        • Slide Number 38
                                                                                                                        • Slide Number 39
                                                                                                                        • Pathophysiology of DIC
                                                                                                                        • Pathogenesis of DIC in Sepsis
                                                                                                                        • Host Response in Severe Sepsis
                                                                                                                        • Organ Failure in Severe Sepsis
                                                                                                                        • Mechanism of DIC in Organ Failure
                                                                                                                        • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                        • Slide Number 47
                                                                                                                        • Diverse and Opposing Effects of Thrombin
                                                                                                                        • Coagulation and Fibrinolysis in DIC
                                                                                                                        • Mechanism of DIC
                                                                                                                        • Pathophysiology of DIC
                                                                                                                        • Pathophysiology of DIC - Mechanism
                                                                                                                        • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                        • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                        • Pathophysiology of Overt DIC
                                                                                                                        • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                        • Slide Number 57
                                                                                                                        • Slide Number 58
                                                                                                                        • Slide Number 59
                                                                                                                        • Slide Number 60
                                                                                                                        • Slide Number 61
                                                                                                                        • BREAK
                                                                                                                        • Diagnostic and Management Approach for DIC
                                                                                                                        • Diagnosis of DIC
                                                                                                                        • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                        • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                        • Slide Number 67
                                                                                                                        • Slide Number 68
                                                                                                                        • British Journal of Haematology Overt DIC Score
                                                                                                                        • Slide Number 70
                                                                                                                        • Slide Number 71
                                                                                                                        • Slide Number 72
                                                                                                                        • Slide Number 73
                                                                                                                        • DIC Management Goals
                                                                                                                        • DIC Management and Treatment
                                                                                                                        • DIC Management Strategies
                                                                                                                        • Anticoagulant Factor Concentrate Treatment
                                                                                                                        • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                        • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                        • D-dimer FDPs and DIC
                                                                                                                        • D-Dimer and FDPs in DIC
                                                                                                                        • Follow Up of DIC State of Disease
                                                                                                                        • FMD-Dimer in DIC Major Differences
                                                                                                                        • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                        • Slide Number 85
                                                                                                                        • Slide Number 86
                                                                                                                        • Comparing an Automated FM vs Manual FSP Test
                                                                                                                        • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                        • Slide Number 94
                                                                                                                        • Slide Number 95
                                                                                                                        • Slide Number 96
                                                                                                                        • Slide Number 97
                                                                                                                        • Slide Number 98
                                                                                                                        • Slide Number 99
                                                                                                                        • DIC Case Studies
                                                                                                                        • Case Study 1 - Presentation
                                                                                                                        • Case Study 1 ndash Lab Results
                                                                                                                        • Case Study 1 ndash Microscopy
                                                                                                                        • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                        • Slide Number 105
                                                                                                                        • Slide Number 106
                                                                                                                        • Slide Number 107
                                                                                                                        • Slide Number 108
                                                                                                                        • Slide Number 109
                                                                                                                        • Slide Number 110
                                                                                                                        • Slide Number 111
                                                                                                                        • Slide Number 112
                                                                                                                        • Slide Number 113
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                                                                                                                        • Slide Number 115
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                                                                                                                        • Slide Number 117
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                                                                                                                        • Slide Number 119
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                                                                                                                        • Slide Number 121
                                                                                                                        • Slide Number 122
                                                                                                                        • Slide Number 123
                                                                                                                        • Slide Number 124
                                                                                                                        • Slide Number 125
                                                                                                                        • DIC Take Home Messages
                                                                                                                        • Slide Number 127
                                                                                                                        • Slide Number 128

                                                                                                                          Stago Educational Apps

                                                                                                                          HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone

                                                                                                                          iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only

                                                                                                                          BREAK

                                                                                                                          Diagnostic and Management Approach for DIC

                                                                                                                          Diagnosis of DIC

                                                                                                                          Clinical diagnosis is obvious in cases of overt DIC

                                                                                                                          Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                                                                                                          Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                                                                                                          Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                                                                                                          Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                                                                                                          Important to recognize simultaneous formation of thrombin and plasmin

                                                                                                                          Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                                                          Lab Diagnosis of DIC ndash Screening Tests

                                                                                                                          Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                                                          Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                                                                                                          fibrinogen level) repeat testing assesses progression

                                                                                                                          Screening tests not clinically specific or sensitive for DIC

                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                          Laboratory Changes in Overt DIC

                                                                                                                          DIC Diagnostic Practices Over Time

                                                                                                                          Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                          British Journal of Haematology Overt DIC Score

                                                                                                                          Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                          ISTH Step by Step DIC Algorithm

                                                                                                                          Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                                                                                          US Based Validation of ISTH DIC Score

                                                                                                                          When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                          Differential Diagnosis in DIC

                                                                                                                          aHUS atypical hemolytic uremic syndrome

                                                                                                                          HUS hemolytic uremic syndrome

                                                                                                                          HIT heparin-induced thrombocytopenia

                                                                                                                          ITP immune thrombocytopenic purpura

                                                                                                                          TTP thrombotic thrombocytopenic purpura

                                                                                                                          DIC and MAHA

                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                          lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                                                                                          When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                                                                                          DIC Management Goals

                                                                                                                          Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                                          Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                                                                                          DIC Management and Treatment

                                                                                                                          Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                                          Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                                                                                          requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                                                                                          Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                                                                                          DIC Management Strategies

                                                                                                                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                          Anticoagulant Factor Concentrate Treatment

                                                                                                                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                          Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                                                                          Anticoagulant Factor Concentrate Treatment Trials

                                                                                                                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                          Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                                                                          Markers of Thrombin amp Plasmin Generation in DIC

                                                                                                                          D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                                                                          Cut-off value

                                                                                                                          Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                                                                          degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                                                                          D-dimer FDPs and DIC

                                                                                                                          D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                                                                          Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                                                                          Follow Up of DIC State of Disease

                                                                                                                          Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                                                                          Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                                                                          FMD-Dimer in DIC Major Differences

                                                                                                                          onset of thrombosis

                                                                                                                          days

                                                                                                                          Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                                                                          FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                                                                          D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                                                                          of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                                                                          0

                                                                                                                          20

                                                                                                                          40

                                                                                                                          60

                                                                                                                          80

                                                                                                                          100

                                                                                                                          94 85 90N = 62

                                                                                                                          Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                                                                          Positivity of Test Results ISTH Score and Disease State

                                                                                                                          Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                          Red bar positive for 2 points of DIC score

                                                                                                                          Pink bar positive for 1-2 points of DIC score

                                                                                                                          HT hematopoietic tumor

                                                                                                                          IF infection

                                                                                                                          SC solid cancer

                                                                                                                          Markers in Patients with or without DIC

                                                                                                                          Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                          HT hematopoietic tumorIF infectionSC solid cancer

                                                                                                                          Comparing an Automated FM vs Manual FSP Test

                                                                                                                          Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                                                          Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                                                          Automated (Mitsubishi) vs Automated (Stago)

                                                                                                                          In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                                                          Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                          In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                          In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                          In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                          Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                          No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                                          Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                          Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                          Non Overt DIC Overt DIC

                                                                                                                          AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                                          Trends in Markers of DIC for Different Patients

                                                                                                                          Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                                          Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                                          Trends in Markers of DIC for Different Patients

                                                                                                                          Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                          FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                                          28 day outcome survival

                                                                                                                          28 day outcome death

                                                                                                                          Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                          Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                          Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                                          Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                          Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                          Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                                          DIC Case Studies

                                                                                                                          Case Study 1 - Presentation

                                                                                                                          18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                          Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                          WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                          RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                          Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                          Hematocrit 195 401 ndash 510

                                                                                                                          MCV 95 fL 790 ndash 922 fL

                                                                                                                          MPV 12 fL 94 ndash 124 fL

                                                                                                                          Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                          Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                          Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                          PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                          APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                          Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                          D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                          Case Study 1 ndash Microscopy

                                                                                                                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                          Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                          Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                          DIC due to TF release by APL blasts

                                                                                                                          Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                          Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                          20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                          Case Study 2 ndash Presentation

                                                                                                                          TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                          PT 30 sec 113 ndash 146 sec

                                                                                                                          APTT 75 sec 25 ndash 34 sec

                                                                                                                          D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                          Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                          pH 728 738 to 742

                                                                                                                          PaO2 570 mmHg 80-100 mmHg

                                                                                                                          WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                          ALT 111 IUL 0ndash34 IUL

                                                                                                                          AST 61 IUL 0ndash34 IUL

                                                                                                                          BUN 303 mgdL 08-13 mgdL

                                                                                                                          Case Study 2 ndash Lab Results

                                                                                                                          Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                          Case Study 2 ndash Diagnosis

                                                                                                                          60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                          Case Study 3 ndash Presentation

                                                                                                                          TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                          PT 228 sec 113 ndash 146 sec

                                                                                                                          APTT 45 sec 25 ndash 34 sec

                                                                                                                          D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                          Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                          FV Normal 70-120

                                                                                                                          FVII Normal 55-170

                                                                                                                          FVIII Normal 60-150

                                                                                                                          Protein C Normal 70-130

                                                                                                                          Hb 134 gdL 14-16 gdL

                                                                                                                          WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                          ALT 32 IUL 0ndash34 IUL

                                                                                                                          AST 28 IUL 0ndash34 IUL

                                                                                                                          BUN 09 mgdL 08-13 mgdL

                                                                                                                          Case Study 3 ndash Lab Results

                                                                                                                          Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                          Case Study 3 ndash Diagnosis and Therapy

                                                                                                                          Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                          Case Study 4 ndash Presentation

                                                                                                                          TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                          PT 28 sec 113 ndash 146 sec

                                                                                                                          APTT 71 sec 25 ndash 34 sec

                                                                                                                          D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                          Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                          FV Normal 70-120

                                                                                                                          FVII Normal 55-170

                                                                                                                          FVIII Normal 60-150

                                                                                                                          Protein C Normal 70-130

                                                                                                                          Hb 158 gdL 14-16 gdL

                                                                                                                          WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                          ALT 60 IUL 0ndash34 IUL

                                                                                                                          AST 47 IUL 0ndash34 IUL

                                                                                                                          BUN 38 mgdL 08-13 mgdL

                                                                                                                          Case Study 4 ndash Lab Results

                                                                                                                          Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                          Case Study 4 ndash Diagnosis

                                                                                                                          55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                          Case Study 5 ndash Presentation

                                                                                                                          Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                          Case Study 5 ndash Lab Results and Time Course

                                                                                                                          Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                          TEST RESULT REFERENCE RANGE

                                                                                                                          Platelet count 33 x 109L 150-450 x 109L

                                                                                                                          PT 215 sec 103 ndash 128 sec

                                                                                                                          APTT 44 sec 26 ndash 36 sec

                                                                                                                          D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                          Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                          FII FV FVIII Low Not reported (NR)

                                                                                                                          FVII FIX FX vWF Normal NR

                                                                                                                          Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                          DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                          dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                          (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                          (D) Illustration demonstrating repair

                                                                                                                          Case Study 5 ndash Diagnosis and Treatment

                                                                                                                          Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                          29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                          Case Study 6 ndash Presentation

                                                                                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                          Case Study 6 ndash Lab Results

                                                                                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                          TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                          PT 63 sec gt control 113 ndash 146 sec

                                                                                                                          INR 658 1 ndash 125

                                                                                                                          APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                          D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                          Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                          Albumin 28 gdL NR

                                                                                                                          Hb 58 gdL NR

                                                                                                                          LDH 1196 UL NR

                                                                                                                          SGPT 144 IU NR

                                                                                                                          SGOT 88 IU NR

                                                                                                                          Bilirubin 32 mgdL NR

                                                                                                                          DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                          day postop

                                                                                                                          Case Study 6 ndash Diagnosis and Treatment

                                                                                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                          HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                          Case Study 6 ndash Discussion

                                                                                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                          44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                          Case Study 7 ndash Presentation

                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                          On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                          Case Study 7 ndash Presentation

                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                          Case Study 7 ndash Lab Results vs Time

                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                          Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                          Case Study 7 ndash Diagnosis and Treatment

                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                          On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                          Case Study 7 ndash Diagnosis and Treatment

                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                          DIC Take Home Messages

                                                                                                                          Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                          Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                          DIC

                                                                                                                          Thank you Questions

                                                                                                                          • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                          • Learning Objectives
                                                                                                                          • Slide Number 3
                                                                                                                          • Slide Number 4
                                                                                                                          • Slide Number 5
                                                                                                                          • Slide Number 6
                                                                                                                          • Slide Number 7
                                                                                                                          • Slide Number 8
                                                                                                                          • Wound Sealing
                                                                                                                          • The Three Steps of Hemostasis
                                                                                                                          • Vessel Wall
                                                                                                                          • Slide Number 12
                                                                                                                          • Slide Number 13
                                                                                                                          • Platelet Structure UnactivatedActivated
                                                                                                                          • Primary Hemostasis
                                                                                                                          • Primary Hemostasis Assays
                                                                                                                          • Slide Number 17
                                                                                                                          • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                          • Slide Number 19
                                                                                                                          • Coagulation factors
                                                                                                                          • Coagulation Assay Mechanisms
                                                                                                                          • Slide Number 22
                                                                                                                          • Fibrin Formation
                                                                                                                          • Slide Number 24
                                                                                                                          • Fibrinolysis Overview
                                                                                                                          • Fibrinolysis Overview
                                                                                                                          • Slide Number 27
                                                                                                                          • Fibrinolysis Releases D-dimers
                                                                                                                          • Basic Pathophysiology of DIC
                                                                                                                          • Disseminated Intravascular Coagulation (DIC)
                                                                                                                          • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                          • Clinical Conditions Associated With DIC
                                                                                                                          • Frequency of DIC in Selected Disease States
                                                                                                                          • Underlying Diseases in DIC Patients
                                                                                                                          • Slide Number 36
                                                                                                                          • Slide Number 37
                                                                                                                          • Slide Number 38
                                                                                                                          • Slide Number 39
                                                                                                                          • Pathophysiology of DIC
                                                                                                                          • Pathogenesis of DIC in Sepsis
                                                                                                                          • Host Response in Severe Sepsis
                                                                                                                          • Organ Failure in Severe Sepsis
                                                                                                                          • Mechanism of DIC in Organ Failure
                                                                                                                          • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                          • Slide Number 47
                                                                                                                          • Diverse and Opposing Effects of Thrombin
                                                                                                                          • Coagulation and Fibrinolysis in DIC
                                                                                                                          • Mechanism of DIC
                                                                                                                          • Pathophysiology of DIC
                                                                                                                          • Pathophysiology of DIC - Mechanism
                                                                                                                          • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                          • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                          • Pathophysiology of Overt DIC
                                                                                                                          • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                          • Slide Number 57
                                                                                                                          • Slide Number 58
                                                                                                                          • Slide Number 59
                                                                                                                          • Slide Number 60
                                                                                                                          • Slide Number 61
                                                                                                                          • BREAK
                                                                                                                          • Diagnostic and Management Approach for DIC
                                                                                                                          • Diagnosis of DIC
                                                                                                                          • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                          • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                          • Slide Number 67
                                                                                                                          • Slide Number 68
                                                                                                                          • British Journal of Haematology Overt DIC Score
                                                                                                                          • Slide Number 70
                                                                                                                          • Slide Number 71
                                                                                                                          • Slide Number 72
                                                                                                                          • Slide Number 73
                                                                                                                          • DIC Management Goals
                                                                                                                          • DIC Management and Treatment
                                                                                                                          • DIC Management Strategies
                                                                                                                          • Anticoagulant Factor Concentrate Treatment
                                                                                                                          • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                          • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                          • D-dimer FDPs and DIC
                                                                                                                          • D-Dimer and FDPs in DIC
                                                                                                                          • Follow Up of DIC State of Disease
                                                                                                                          • FMD-Dimer in DIC Major Differences
                                                                                                                          • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                          • Slide Number 85
                                                                                                                          • Slide Number 86
                                                                                                                          • Comparing an Automated FM vs Manual FSP Test
                                                                                                                          • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                          • Slide Number 94
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                                                                                                                          • DIC Case Studies
                                                                                                                          • Case Study 1 - Presentation
                                                                                                                          • Case Study 1 ndash Lab Results
                                                                                                                          • Case Study 1 ndash Microscopy
                                                                                                                          • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                          • Slide Number 105
                                                                                                                          • Slide Number 106
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                                                                                                                          • Slide Number 125
                                                                                                                          • DIC Take Home Messages
                                                                                                                          • Slide Number 127
                                                                                                                          • Slide Number 128

                                                                                                                            BREAK

                                                                                                                            Diagnostic and Management Approach for DIC

                                                                                                                            Diagnosis of DIC

                                                                                                                            Clinical diagnosis is obvious in cases of overt DIC

                                                                                                                            Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                                                                                                            Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                                                                                                            Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                                                                                                            Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                                                                                                            Important to recognize simultaneous formation of thrombin and plasmin

                                                                                                                            Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                                                            Lab Diagnosis of DIC ndash Screening Tests

                                                                                                                            Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                                                            Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                                                                                                            fibrinogen level) repeat testing assesses progression

                                                                                                                            Screening tests not clinically specific or sensitive for DIC

                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                            Laboratory Changes in Overt DIC

                                                                                                                            DIC Diagnostic Practices Over Time

                                                                                                                            Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                            British Journal of Haematology Overt DIC Score

                                                                                                                            Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                            ISTH Step by Step DIC Algorithm

                                                                                                                            Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                                                                                            US Based Validation of ISTH DIC Score

                                                                                                                            When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                            Differential Diagnosis in DIC

                                                                                                                            aHUS atypical hemolytic uremic syndrome

                                                                                                                            HUS hemolytic uremic syndrome

                                                                                                                            HIT heparin-induced thrombocytopenia

                                                                                                                            ITP immune thrombocytopenic purpura

                                                                                                                            TTP thrombotic thrombocytopenic purpura

                                                                                                                            DIC and MAHA

                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                            lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                                                                                            When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                                                                                            DIC Management Goals

                                                                                                                            Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                                            Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                                                                                            DIC Management and Treatment

                                                                                                                            Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                                            Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                                                                                            requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                                                                                            Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                                                                                            DIC Management Strategies

                                                                                                                            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                            Anticoagulant Factor Concentrate Treatment

                                                                                                                            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                            Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                                                                            Anticoagulant Factor Concentrate Treatment Trials

                                                                                                                            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                            Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                                                                            Markers of Thrombin amp Plasmin Generation in DIC

                                                                                                                            D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                                                                            Cut-off value

                                                                                                                            Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                                                                            degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                                                                            D-dimer FDPs and DIC

                                                                                                                            D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                                                                            Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                                                                            Follow Up of DIC State of Disease

                                                                                                                            Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                                                                            Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                                                                            FMD-Dimer in DIC Major Differences

                                                                                                                            onset of thrombosis

                                                                                                                            days

                                                                                                                            Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                                                                            FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                                                                            D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                                                                            of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                                                                            0

                                                                                                                            20

                                                                                                                            40

                                                                                                                            60

                                                                                                                            80

                                                                                                                            100

                                                                                                                            94 85 90N = 62

                                                                                                                            Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                                                                            Positivity of Test Results ISTH Score and Disease State

                                                                                                                            Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                            Red bar positive for 2 points of DIC score

                                                                                                                            Pink bar positive for 1-2 points of DIC score

                                                                                                                            HT hematopoietic tumor

                                                                                                                            IF infection

                                                                                                                            SC solid cancer

                                                                                                                            Markers in Patients with or without DIC

                                                                                                                            Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                            HT hematopoietic tumorIF infectionSC solid cancer

                                                                                                                            Comparing an Automated FM vs Manual FSP Test

                                                                                                                            Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                                                            Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                                                            Automated (Mitsubishi) vs Automated (Stago)

                                                                                                                            In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                                                            Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                            In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                            In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                            In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                            Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                            No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                                            Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                            Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                            Non Overt DIC Overt DIC

                                                                                                                            AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                                            Trends in Markers of DIC for Different Patients

                                                                                                                            Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                                            Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                                            Trends in Markers of DIC for Different Patients

                                                                                                                            Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                            FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                                            28 day outcome survival

                                                                                                                            28 day outcome death

                                                                                                                            Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                            Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                            Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                                            Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                            Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                            Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                                            DIC Case Studies

                                                                                                                            Case Study 1 - Presentation

                                                                                                                            18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                            Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                            WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                            RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                            Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                            Hematocrit 195 401 ndash 510

                                                                                                                            MCV 95 fL 790 ndash 922 fL

                                                                                                                            MPV 12 fL 94 ndash 124 fL

                                                                                                                            Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                            Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                            Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                            PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                            APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                            Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                            D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                            Case Study 1 ndash Microscopy

                                                                                                                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                            Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                            Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                            DIC due to TF release by APL blasts

                                                                                                                            Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                            Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                            20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                            Case Study 2 ndash Presentation

                                                                                                                            TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                            PT 30 sec 113 ndash 146 sec

                                                                                                                            APTT 75 sec 25 ndash 34 sec

                                                                                                                            D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                            Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                            pH 728 738 to 742

                                                                                                                            PaO2 570 mmHg 80-100 mmHg

                                                                                                                            WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                            ALT 111 IUL 0ndash34 IUL

                                                                                                                            AST 61 IUL 0ndash34 IUL

                                                                                                                            BUN 303 mgdL 08-13 mgdL

                                                                                                                            Case Study 2 ndash Lab Results

                                                                                                                            Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                            Case Study 2 ndash Diagnosis

                                                                                                                            60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                            Case Study 3 ndash Presentation

                                                                                                                            TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                            PT 228 sec 113 ndash 146 sec

                                                                                                                            APTT 45 sec 25 ndash 34 sec

                                                                                                                            D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                            Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                            FV Normal 70-120

                                                                                                                            FVII Normal 55-170

                                                                                                                            FVIII Normal 60-150

                                                                                                                            Protein C Normal 70-130

                                                                                                                            Hb 134 gdL 14-16 gdL

                                                                                                                            WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                            ALT 32 IUL 0ndash34 IUL

                                                                                                                            AST 28 IUL 0ndash34 IUL

                                                                                                                            BUN 09 mgdL 08-13 mgdL

                                                                                                                            Case Study 3 ndash Lab Results

                                                                                                                            Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                            Case Study 3 ndash Diagnosis and Therapy

                                                                                                                            Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                            Case Study 4 ndash Presentation

                                                                                                                            TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                            PT 28 sec 113 ndash 146 sec

                                                                                                                            APTT 71 sec 25 ndash 34 sec

                                                                                                                            D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                            Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                            FV Normal 70-120

                                                                                                                            FVII Normal 55-170

                                                                                                                            FVIII Normal 60-150

                                                                                                                            Protein C Normal 70-130

                                                                                                                            Hb 158 gdL 14-16 gdL

                                                                                                                            WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                            ALT 60 IUL 0ndash34 IUL

                                                                                                                            AST 47 IUL 0ndash34 IUL

                                                                                                                            BUN 38 mgdL 08-13 mgdL

                                                                                                                            Case Study 4 ndash Lab Results

                                                                                                                            Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                            Case Study 4 ndash Diagnosis

                                                                                                                            55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                            Case Study 5 ndash Presentation

                                                                                                                            Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                            Case Study 5 ndash Lab Results and Time Course

                                                                                                                            Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                            TEST RESULT REFERENCE RANGE

                                                                                                                            Platelet count 33 x 109L 150-450 x 109L

                                                                                                                            PT 215 sec 103 ndash 128 sec

                                                                                                                            APTT 44 sec 26 ndash 36 sec

                                                                                                                            D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                            Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                            FII FV FVIII Low Not reported (NR)

                                                                                                                            FVII FIX FX vWF Normal NR

                                                                                                                            Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                            DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                            dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                            (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                            (D) Illustration demonstrating repair

                                                                                                                            Case Study 5 ndash Diagnosis and Treatment

                                                                                                                            Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                            29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                            Case Study 6 ndash Presentation

                                                                                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                            Case Study 6 ndash Lab Results

                                                                                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                            TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                            PT 63 sec gt control 113 ndash 146 sec

                                                                                                                            INR 658 1 ndash 125

                                                                                                                            APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                            D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                            Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                            Albumin 28 gdL NR

                                                                                                                            Hb 58 gdL NR

                                                                                                                            LDH 1196 UL NR

                                                                                                                            SGPT 144 IU NR

                                                                                                                            SGOT 88 IU NR

                                                                                                                            Bilirubin 32 mgdL NR

                                                                                                                            DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                            day postop

                                                                                                                            Case Study 6 ndash Diagnosis and Treatment

                                                                                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                            HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                            Case Study 6 ndash Discussion

                                                                                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                            44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                            Case Study 7 ndash Presentation

                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                            On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                            Case Study 7 ndash Presentation

                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                            Case Study 7 ndash Lab Results vs Time

                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                            Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                            Case Study 7 ndash Diagnosis and Treatment

                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                            On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                            Case Study 7 ndash Diagnosis and Treatment

                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                            DIC Take Home Messages

                                                                                                                            Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                            Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                            DIC

                                                                                                                            Thank you Questions

                                                                                                                            • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                            • Learning Objectives
                                                                                                                            • Slide Number 3
                                                                                                                            • Slide Number 4
                                                                                                                            • Slide Number 5
                                                                                                                            • Slide Number 6
                                                                                                                            • Slide Number 7
                                                                                                                            • Slide Number 8
                                                                                                                            • Wound Sealing
                                                                                                                            • The Three Steps of Hemostasis
                                                                                                                            • Vessel Wall
                                                                                                                            • Slide Number 12
                                                                                                                            • Slide Number 13
                                                                                                                            • Platelet Structure UnactivatedActivated
                                                                                                                            • Primary Hemostasis
                                                                                                                            • Primary Hemostasis Assays
                                                                                                                            • Slide Number 17
                                                                                                                            • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                            • Slide Number 19
                                                                                                                            • Coagulation factors
                                                                                                                            • Coagulation Assay Mechanisms
                                                                                                                            • Slide Number 22
                                                                                                                            • Fibrin Formation
                                                                                                                            • Slide Number 24
                                                                                                                            • Fibrinolysis Overview
                                                                                                                            • Fibrinolysis Overview
                                                                                                                            • Slide Number 27
                                                                                                                            • Fibrinolysis Releases D-dimers
                                                                                                                            • Basic Pathophysiology of DIC
                                                                                                                            • Disseminated Intravascular Coagulation (DIC)
                                                                                                                            • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                            • Clinical Conditions Associated With DIC
                                                                                                                            • Frequency of DIC in Selected Disease States
                                                                                                                            • Underlying Diseases in DIC Patients
                                                                                                                            • Slide Number 36
                                                                                                                            • Slide Number 37
                                                                                                                            • Slide Number 38
                                                                                                                            • Slide Number 39
                                                                                                                            • Pathophysiology of DIC
                                                                                                                            • Pathogenesis of DIC in Sepsis
                                                                                                                            • Host Response in Severe Sepsis
                                                                                                                            • Organ Failure in Severe Sepsis
                                                                                                                            • Mechanism of DIC in Organ Failure
                                                                                                                            • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                            • Slide Number 47
                                                                                                                            • Diverse and Opposing Effects of Thrombin
                                                                                                                            • Coagulation and Fibrinolysis in DIC
                                                                                                                            • Mechanism of DIC
                                                                                                                            • Pathophysiology of DIC
                                                                                                                            • Pathophysiology of DIC - Mechanism
                                                                                                                            • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                            • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                            • Pathophysiology of Overt DIC
                                                                                                                            • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                            • Slide Number 57
                                                                                                                            • Slide Number 58
                                                                                                                            • Slide Number 59
                                                                                                                            • Slide Number 60
                                                                                                                            • Slide Number 61
                                                                                                                            • BREAK
                                                                                                                            • Diagnostic and Management Approach for DIC
                                                                                                                            • Diagnosis of DIC
                                                                                                                            • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                            • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                            • Slide Number 67
                                                                                                                            • Slide Number 68
                                                                                                                            • British Journal of Haematology Overt DIC Score
                                                                                                                            • Slide Number 70
                                                                                                                            • Slide Number 71
                                                                                                                            • Slide Number 72
                                                                                                                            • Slide Number 73
                                                                                                                            • DIC Management Goals
                                                                                                                            • DIC Management and Treatment
                                                                                                                            • DIC Management Strategies
                                                                                                                            • Anticoagulant Factor Concentrate Treatment
                                                                                                                            • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                            • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                            • D-dimer FDPs and DIC
                                                                                                                            • D-Dimer and FDPs in DIC
                                                                                                                            • Follow Up of DIC State of Disease
                                                                                                                            • FMD-Dimer in DIC Major Differences
                                                                                                                            • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                            • Slide Number 85
                                                                                                                            • Slide Number 86
                                                                                                                            • Comparing an Automated FM vs Manual FSP Test
                                                                                                                            • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                            • Slide Number 94
                                                                                                                            • Slide Number 95
                                                                                                                            • Slide Number 96
                                                                                                                            • Slide Number 97
                                                                                                                            • Slide Number 98
                                                                                                                            • Slide Number 99
                                                                                                                            • DIC Case Studies
                                                                                                                            • Case Study 1 - Presentation
                                                                                                                            • Case Study 1 ndash Lab Results
                                                                                                                            • Case Study 1 ndash Microscopy
                                                                                                                            • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                            • Slide Number 105
                                                                                                                            • Slide Number 106
                                                                                                                            • Slide Number 107
                                                                                                                            • Slide Number 108
                                                                                                                            • Slide Number 109
                                                                                                                            • Slide Number 110
                                                                                                                            • Slide Number 111
                                                                                                                            • Slide Number 112
                                                                                                                            • Slide Number 113
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                                                                                                                            • Slide Number 120
                                                                                                                            • Slide Number 121
                                                                                                                            • Slide Number 122
                                                                                                                            • Slide Number 123
                                                                                                                            • Slide Number 124
                                                                                                                            • Slide Number 125
                                                                                                                            • DIC Take Home Messages
                                                                                                                            • Slide Number 127
                                                                                                                            • Slide Number 128

                                                                                                                              Diagnostic and Management Approach for DIC

                                                                                                                              Diagnosis of DIC

                                                                                                                              Clinical diagnosis is obvious in cases of overt DIC

                                                                                                                              Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                                                                                                              Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                                                                                                              Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                                                                                                              Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                                                                                                              Important to recognize simultaneous formation of thrombin and plasmin

                                                                                                                              Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                                                              Lab Diagnosis of DIC ndash Screening Tests

                                                                                                                              Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                                                              Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                                                                                                              fibrinogen level) repeat testing assesses progression

                                                                                                                              Screening tests not clinically specific or sensitive for DIC

                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                              Laboratory Changes in Overt DIC

                                                                                                                              DIC Diagnostic Practices Over Time

                                                                                                                              Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                              British Journal of Haematology Overt DIC Score

                                                                                                                              Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                              ISTH Step by Step DIC Algorithm

                                                                                                                              Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                                                                                              US Based Validation of ISTH DIC Score

                                                                                                                              When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                              Differential Diagnosis in DIC

                                                                                                                              aHUS atypical hemolytic uremic syndrome

                                                                                                                              HUS hemolytic uremic syndrome

                                                                                                                              HIT heparin-induced thrombocytopenia

                                                                                                                              ITP immune thrombocytopenic purpura

                                                                                                                              TTP thrombotic thrombocytopenic purpura

                                                                                                                              DIC and MAHA

                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                              lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                                                                                              When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                                                                                              DIC Management Goals

                                                                                                                              Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                                              Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                                                                                              DIC Management and Treatment

                                                                                                                              Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                                              Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                                                                                              requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                                                                                              Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                                                                                              DIC Management Strategies

                                                                                                                              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                              Anticoagulant Factor Concentrate Treatment

                                                                                                                              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                              Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                                                                              Anticoagulant Factor Concentrate Treatment Trials

                                                                                                                              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                              Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                                                                              Markers of Thrombin amp Plasmin Generation in DIC

                                                                                                                              D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                                                                              Cut-off value

                                                                                                                              Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                                                                              degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                                                                              D-dimer FDPs and DIC

                                                                                                                              D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                                                                              Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                                                                              Follow Up of DIC State of Disease

                                                                                                                              Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                                                                              Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                                                                              FMD-Dimer in DIC Major Differences

                                                                                                                              onset of thrombosis

                                                                                                                              days

                                                                                                                              Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                                                                              FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                                                                              D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                                                                              of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                                                                              0

                                                                                                                              20

                                                                                                                              40

                                                                                                                              60

                                                                                                                              80

                                                                                                                              100

                                                                                                                              94 85 90N = 62

                                                                                                                              Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                                                                              Positivity of Test Results ISTH Score and Disease State

                                                                                                                              Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                              Red bar positive for 2 points of DIC score

                                                                                                                              Pink bar positive for 1-2 points of DIC score

                                                                                                                              HT hematopoietic tumor

                                                                                                                              IF infection

                                                                                                                              SC solid cancer

                                                                                                                              Markers in Patients with or without DIC

                                                                                                                              Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                              HT hematopoietic tumorIF infectionSC solid cancer

                                                                                                                              Comparing an Automated FM vs Manual FSP Test

                                                                                                                              Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                                                              Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                                                              Automated (Mitsubishi) vs Automated (Stago)

                                                                                                                              In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                                                              Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                              In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                              In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                              In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                              Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                              No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                                              Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                              Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                              Non Overt DIC Overt DIC

                                                                                                                              AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                                              Trends in Markers of DIC for Different Patients

                                                                                                                              Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                                              Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                                              Trends in Markers of DIC for Different Patients

                                                                                                                              Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                              FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                                              28 day outcome survival

                                                                                                                              28 day outcome death

                                                                                                                              Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                              Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                              Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                                              Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                              Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                              Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                                              DIC Case Studies

                                                                                                                              Case Study 1 - Presentation

                                                                                                                              18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                              Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                              WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                              RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                              Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                              Hematocrit 195 401 ndash 510

                                                                                                                              MCV 95 fL 790 ndash 922 fL

                                                                                                                              MPV 12 fL 94 ndash 124 fL

                                                                                                                              Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                              Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                              Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                              PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                              APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                              Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                              D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                              Case Study 1 ndash Microscopy

                                                                                                                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                              Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                              Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                              DIC due to TF release by APL blasts

                                                                                                                              Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                              Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                              20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                              Case Study 2 ndash Presentation

                                                                                                                              TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                              PT 30 sec 113 ndash 146 sec

                                                                                                                              APTT 75 sec 25 ndash 34 sec

                                                                                                                              D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                              Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                              pH 728 738 to 742

                                                                                                                              PaO2 570 mmHg 80-100 mmHg

                                                                                                                              WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                              ALT 111 IUL 0ndash34 IUL

                                                                                                                              AST 61 IUL 0ndash34 IUL

                                                                                                                              BUN 303 mgdL 08-13 mgdL

                                                                                                                              Case Study 2 ndash Lab Results

                                                                                                                              Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                              Case Study 2 ndash Diagnosis

                                                                                                                              60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                              Case Study 3 ndash Presentation

                                                                                                                              TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                              PT 228 sec 113 ndash 146 sec

                                                                                                                              APTT 45 sec 25 ndash 34 sec

                                                                                                                              D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                              Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                              FV Normal 70-120

                                                                                                                              FVII Normal 55-170

                                                                                                                              FVIII Normal 60-150

                                                                                                                              Protein C Normal 70-130

                                                                                                                              Hb 134 gdL 14-16 gdL

                                                                                                                              WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                              ALT 32 IUL 0ndash34 IUL

                                                                                                                              AST 28 IUL 0ndash34 IUL

                                                                                                                              BUN 09 mgdL 08-13 mgdL

                                                                                                                              Case Study 3 ndash Lab Results

                                                                                                                              Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                              Case Study 3 ndash Diagnosis and Therapy

                                                                                                                              Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                              Case Study 4 ndash Presentation

                                                                                                                              TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                              PT 28 sec 113 ndash 146 sec

                                                                                                                              APTT 71 sec 25 ndash 34 sec

                                                                                                                              D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                              Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                              FV Normal 70-120

                                                                                                                              FVII Normal 55-170

                                                                                                                              FVIII Normal 60-150

                                                                                                                              Protein C Normal 70-130

                                                                                                                              Hb 158 gdL 14-16 gdL

                                                                                                                              WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                              ALT 60 IUL 0ndash34 IUL

                                                                                                                              AST 47 IUL 0ndash34 IUL

                                                                                                                              BUN 38 mgdL 08-13 mgdL

                                                                                                                              Case Study 4 ndash Lab Results

                                                                                                                              Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                              Case Study 4 ndash Diagnosis

                                                                                                                              55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                              Case Study 5 ndash Presentation

                                                                                                                              Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                              Case Study 5 ndash Lab Results and Time Course

                                                                                                                              Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                              TEST RESULT REFERENCE RANGE

                                                                                                                              Platelet count 33 x 109L 150-450 x 109L

                                                                                                                              PT 215 sec 103 ndash 128 sec

                                                                                                                              APTT 44 sec 26 ndash 36 sec

                                                                                                                              D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                              Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                              FII FV FVIII Low Not reported (NR)

                                                                                                                              FVII FIX FX vWF Normal NR

                                                                                                                              Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                              DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                              dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                              (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                              (D) Illustration demonstrating repair

                                                                                                                              Case Study 5 ndash Diagnosis and Treatment

                                                                                                                              Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                              29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                              Case Study 6 ndash Presentation

                                                                                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                              Case Study 6 ndash Lab Results

                                                                                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                              TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                              PT 63 sec gt control 113 ndash 146 sec

                                                                                                                              INR 658 1 ndash 125

                                                                                                                              APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                              D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                              Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                              Albumin 28 gdL NR

                                                                                                                              Hb 58 gdL NR

                                                                                                                              LDH 1196 UL NR

                                                                                                                              SGPT 144 IU NR

                                                                                                                              SGOT 88 IU NR

                                                                                                                              Bilirubin 32 mgdL NR

                                                                                                                              DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                              day postop

                                                                                                                              Case Study 6 ndash Diagnosis and Treatment

                                                                                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                              HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                              Case Study 6 ndash Discussion

                                                                                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                              44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                              Case Study 7 ndash Presentation

                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                              On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                              Case Study 7 ndash Presentation

                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                              Case Study 7 ndash Lab Results vs Time

                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                              Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                              Case Study 7 ndash Diagnosis and Treatment

                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                              On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                              Case Study 7 ndash Diagnosis and Treatment

                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                              DIC Take Home Messages

                                                                                                                              Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                              Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                              DIC

                                                                                                                              Thank you Questions

                                                                                                                              • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                              • Learning Objectives
                                                                                                                              • Slide Number 3
                                                                                                                              • Slide Number 4
                                                                                                                              • Slide Number 5
                                                                                                                              • Slide Number 6
                                                                                                                              • Slide Number 7
                                                                                                                              • Slide Number 8
                                                                                                                              • Wound Sealing
                                                                                                                              • The Three Steps of Hemostasis
                                                                                                                              • Vessel Wall
                                                                                                                              • Slide Number 12
                                                                                                                              • Slide Number 13
                                                                                                                              • Platelet Structure UnactivatedActivated
                                                                                                                              • Primary Hemostasis
                                                                                                                              • Primary Hemostasis Assays
                                                                                                                              • Slide Number 17
                                                                                                                              • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                              • Slide Number 19
                                                                                                                              • Coagulation factors
                                                                                                                              • Coagulation Assay Mechanisms
                                                                                                                              • Slide Number 22
                                                                                                                              • Fibrin Formation
                                                                                                                              • Slide Number 24
                                                                                                                              • Fibrinolysis Overview
                                                                                                                              • Fibrinolysis Overview
                                                                                                                              • Slide Number 27
                                                                                                                              • Fibrinolysis Releases D-dimers
                                                                                                                              • Basic Pathophysiology of DIC
                                                                                                                              • Disseminated Intravascular Coagulation (DIC)
                                                                                                                              • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                              • Clinical Conditions Associated With DIC
                                                                                                                              • Frequency of DIC in Selected Disease States
                                                                                                                              • Underlying Diseases in DIC Patients
                                                                                                                              • Slide Number 36
                                                                                                                              • Slide Number 37
                                                                                                                              • Slide Number 38
                                                                                                                              • Slide Number 39
                                                                                                                              • Pathophysiology of DIC
                                                                                                                              • Pathogenesis of DIC in Sepsis
                                                                                                                              • Host Response in Severe Sepsis
                                                                                                                              • Organ Failure in Severe Sepsis
                                                                                                                              • Mechanism of DIC in Organ Failure
                                                                                                                              • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                              • Slide Number 47
                                                                                                                              • Diverse and Opposing Effects of Thrombin
                                                                                                                              • Coagulation and Fibrinolysis in DIC
                                                                                                                              • Mechanism of DIC
                                                                                                                              • Pathophysiology of DIC
                                                                                                                              • Pathophysiology of DIC - Mechanism
                                                                                                                              • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                              • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                              • Pathophysiology of Overt DIC
                                                                                                                              • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                              • Slide Number 57
                                                                                                                              • Slide Number 58
                                                                                                                              • Slide Number 59
                                                                                                                              • Slide Number 60
                                                                                                                              • Slide Number 61
                                                                                                                              • BREAK
                                                                                                                              • Diagnostic and Management Approach for DIC
                                                                                                                              • Diagnosis of DIC
                                                                                                                              • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                              • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                              • Slide Number 67
                                                                                                                              • Slide Number 68
                                                                                                                              • British Journal of Haematology Overt DIC Score
                                                                                                                              • Slide Number 70
                                                                                                                              • Slide Number 71
                                                                                                                              • Slide Number 72
                                                                                                                              • Slide Number 73
                                                                                                                              • DIC Management Goals
                                                                                                                              • DIC Management and Treatment
                                                                                                                              • DIC Management Strategies
                                                                                                                              • Anticoagulant Factor Concentrate Treatment
                                                                                                                              • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                              • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                              • D-dimer FDPs and DIC
                                                                                                                              • D-Dimer and FDPs in DIC
                                                                                                                              • Follow Up of DIC State of Disease
                                                                                                                              • FMD-Dimer in DIC Major Differences
                                                                                                                              • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                              • Slide Number 85
                                                                                                                              • Slide Number 86
                                                                                                                              • Comparing an Automated FM vs Manual FSP Test
                                                                                                                              • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                              • Slide Number 94
                                                                                                                              • Slide Number 95
                                                                                                                              • Slide Number 96
                                                                                                                              • Slide Number 97
                                                                                                                              • Slide Number 98
                                                                                                                              • Slide Number 99
                                                                                                                              • DIC Case Studies
                                                                                                                              • Case Study 1 - Presentation
                                                                                                                              • Case Study 1 ndash Lab Results
                                                                                                                              • Case Study 1 ndash Microscopy
                                                                                                                              • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                              • Slide Number 105
                                                                                                                              • Slide Number 106
                                                                                                                              • Slide Number 107
                                                                                                                              • Slide Number 108
                                                                                                                              • Slide Number 109
                                                                                                                              • Slide Number 110
                                                                                                                              • Slide Number 111
                                                                                                                              • Slide Number 112
                                                                                                                              • Slide Number 113
                                                                                                                              • Slide Number 114
                                                                                                                              • Slide Number 115
                                                                                                                              • Slide Number 116
                                                                                                                              • Slide Number 117
                                                                                                                              • Slide Number 118
                                                                                                                              • Slide Number 119
                                                                                                                              • Slide Number 120
                                                                                                                              • Slide Number 121
                                                                                                                              • Slide Number 122
                                                                                                                              • Slide Number 123
                                                                                                                              • Slide Number 124
                                                                                                                              • Slide Number 125
                                                                                                                              • DIC Take Home Messages
                                                                                                                              • Slide Number 127
                                                                                                                              • Slide Number 128

                                                                                                                                Diagnosis of DIC

                                                                                                                                Clinical diagnosis is obvious in cases of overt DIC

                                                                                                                                Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy

                                                                                                                                Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                                                                                                                Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                                                                                                                Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                                                                                                                Important to recognize simultaneous formation of thrombin and plasmin

                                                                                                                                Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                                                                Lab Diagnosis of DIC ndash Screening Tests

                                                                                                                                Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                                                                Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                                                                                                                fibrinogen level) repeat testing assesses progression

                                                                                                                                Screening tests not clinically specific or sensitive for DIC

                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                Laboratory Changes in Overt DIC

                                                                                                                                DIC Diagnostic Practices Over Time

                                                                                                                                Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                British Journal of Haematology Overt DIC Score

                                                                                                                                Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                ISTH Step by Step DIC Algorithm

                                                                                                                                Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                                                                                                US Based Validation of ISTH DIC Score

                                                                                                                                When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                Differential Diagnosis in DIC

                                                                                                                                aHUS atypical hemolytic uremic syndrome

                                                                                                                                HUS hemolytic uremic syndrome

                                                                                                                                HIT heparin-induced thrombocytopenia

                                                                                                                                ITP immune thrombocytopenic purpura

                                                                                                                                TTP thrombotic thrombocytopenic purpura

                                                                                                                                DIC and MAHA

                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                                                                                                When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                                                                                                DIC Management Goals

                                                                                                                                Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                                                Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                                                                                                DIC Management and Treatment

                                                                                                                                Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                                                Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                                                                                                requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                                                                                                Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                                                                                                DIC Management Strategies

                                                                                                                                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                                Anticoagulant Factor Concentrate Treatment

                                                                                                                                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                                Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                                                                                Anticoagulant Factor Concentrate Treatment Trials

                                                                                                                                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                                Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                                                                                Markers of Thrombin amp Plasmin Generation in DIC

                                                                                                                                D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                                                                                Cut-off value

                                                                                                                                Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                                                                                degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                                                                                D-dimer FDPs and DIC

                                                                                                                                D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                                                                                Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                                                                                Follow Up of DIC State of Disease

                                                                                                                                Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                                                                                Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                                                                                FMD-Dimer in DIC Major Differences

                                                                                                                                onset of thrombosis

                                                                                                                                days

                                                                                                                                Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                                                                                FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                                                                                D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                                                                                of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                                                                                0

                                                                                                                                20

                                                                                                                                40

                                                                                                                                60

                                                                                                                                80

                                                                                                                                100

                                                                                                                                94 85 90N = 62

                                                                                                                                Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                                                                                Positivity of Test Results ISTH Score and Disease State

                                                                                                                                Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                Red bar positive for 2 points of DIC score

                                                                                                                                Pink bar positive for 1-2 points of DIC score

                                                                                                                                HT hematopoietic tumor

                                                                                                                                IF infection

                                                                                                                                SC solid cancer

                                                                                                                                Markers in Patients with or without DIC

                                                                                                                                Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                HT hematopoietic tumorIF infectionSC solid cancer

                                                                                                                                Comparing an Automated FM vs Manual FSP Test

                                                                                                                                Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                                                                Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                                                                Automated (Mitsubishi) vs Automated (Stago)

                                                                                                                                In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                                                                Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                                                Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                Non Overt DIC Overt DIC

                                                                                                                                AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                                                Trends in Markers of DIC for Different Patients

                                                                                                                                Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                                                Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                                                Trends in Markers of DIC for Different Patients

                                                                                                                                Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                                                28 day outcome survival

                                                                                                                                28 day outcome death

                                                                                                                                Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                                                Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                                                DIC Case Studies

                                                                                                                                Case Study 1 - Presentation

                                                                                                                                18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                                WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                                RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                                Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                                Hematocrit 195 401 ndash 510

                                                                                                                                MCV 95 fL 790 ndash 922 fL

                                                                                                                                MPV 12 fL 94 ndash 124 fL

                                                                                                                                Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                                Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                                Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                                PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                                APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                                Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                                D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                Case Study 1 ndash Microscopy

                                                                                                                                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                                Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                                DIC due to TF release by APL blasts

                                                                                                                                Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                                Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                                Case Study 2 ndash Presentation

                                                                                                                                TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                                PT 30 sec 113 ndash 146 sec

                                                                                                                                APTT 75 sec 25 ndash 34 sec

                                                                                                                                D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                                Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                                pH 728 738 to 742

                                                                                                                                PaO2 570 mmHg 80-100 mmHg

                                                                                                                                WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                                ALT 111 IUL 0ndash34 IUL

                                                                                                                                AST 61 IUL 0ndash34 IUL

                                                                                                                                BUN 303 mgdL 08-13 mgdL

                                                                                                                                Case Study 2 ndash Lab Results

                                                                                                                                Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                                Case Study 2 ndash Diagnosis

                                                                                                                                60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                                Case Study 3 ndash Presentation

                                                                                                                                TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                PT 228 sec 113 ndash 146 sec

                                                                                                                                APTT 45 sec 25 ndash 34 sec

                                                                                                                                D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                FV Normal 70-120

                                                                                                                                FVII Normal 55-170

                                                                                                                                FVIII Normal 60-150

                                                                                                                                Protein C Normal 70-130

                                                                                                                                Hb 134 gdL 14-16 gdL

                                                                                                                                WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                ALT 32 IUL 0ndash34 IUL

                                                                                                                                AST 28 IUL 0ndash34 IUL

                                                                                                                                BUN 09 mgdL 08-13 mgdL

                                                                                                                                Case Study 3 ndash Lab Results

                                                                                                                                Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                Case Study 4 ndash Presentation

                                                                                                                                TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                PT 28 sec 113 ndash 146 sec

                                                                                                                                APTT 71 sec 25 ndash 34 sec

                                                                                                                                D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                FV Normal 70-120

                                                                                                                                FVII Normal 55-170

                                                                                                                                FVIII Normal 60-150

                                                                                                                                Protein C Normal 70-130

                                                                                                                                Hb 158 gdL 14-16 gdL

                                                                                                                                WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                ALT 60 IUL 0ndash34 IUL

                                                                                                                                AST 47 IUL 0ndash34 IUL

                                                                                                                                BUN 38 mgdL 08-13 mgdL

                                                                                                                                Case Study 4 ndash Lab Results

                                                                                                                                Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                Case Study 4 ndash Diagnosis

                                                                                                                                55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                Case Study 5 ndash Presentation

                                                                                                                                Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                Case Study 5 ndash Lab Results and Time Course

                                                                                                                                Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                TEST RESULT REFERENCE RANGE

                                                                                                                                Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                PT 215 sec 103 ndash 128 sec

                                                                                                                                APTT 44 sec 26 ndash 36 sec

                                                                                                                                D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                FII FV FVIII Low Not reported (NR)

                                                                                                                                FVII FIX FX vWF Normal NR

                                                                                                                                Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                (D) Illustration demonstrating repair

                                                                                                                                Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                Case Study 6 ndash Presentation

                                                                                                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                Case Study 6 ndash Lab Results

                                                                                                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                INR 658 1 ndash 125

                                                                                                                                APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                Albumin 28 gdL NR

                                                                                                                                Hb 58 gdL NR

                                                                                                                                LDH 1196 UL NR

                                                                                                                                SGPT 144 IU NR

                                                                                                                                SGOT 88 IU NR

                                                                                                                                Bilirubin 32 mgdL NR

                                                                                                                                DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                day postop

                                                                                                                                Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                Case Study 6 ndash Discussion

                                                                                                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                Case Study 7 ndash Presentation

                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                Case Study 7 ndash Presentation

                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                Case Study 7 ndash Lab Results vs Time

                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                DIC Take Home Messages

                                                                                                                                Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                DIC

                                                                                                                                Thank you Questions

                                                                                                                                • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                • Learning Objectives
                                                                                                                                • Slide Number 3
                                                                                                                                • Slide Number 4
                                                                                                                                • Slide Number 5
                                                                                                                                • Slide Number 6
                                                                                                                                • Slide Number 7
                                                                                                                                • Slide Number 8
                                                                                                                                • Wound Sealing
                                                                                                                                • The Three Steps of Hemostasis
                                                                                                                                • Vessel Wall
                                                                                                                                • Slide Number 12
                                                                                                                                • Slide Number 13
                                                                                                                                • Platelet Structure UnactivatedActivated
                                                                                                                                • Primary Hemostasis
                                                                                                                                • Primary Hemostasis Assays
                                                                                                                                • Slide Number 17
                                                                                                                                • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                • Slide Number 19
                                                                                                                                • Coagulation factors
                                                                                                                                • Coagulation Assay Mechanisms
                                                                                                                                • Slide Number 22
                                                                                                                                • Fibrin Formation
                                                                                                                                • Slide Number 24
                                                                                                                                • Fibrinolysis Overview
                                                                                                                                • Fibrinolysis Overview
                                                                                                                                • Slide Number 27
                                                                                                                                • Fibrinolysis Releases D-dimers
                                                                                                                                • Basic Pathophysiology of DIC
                                                                                                                                • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                • Clinical Conditions Associated With DIC
                                                                                                                                • Frequency of DIC in Selected Disease States
                                                                                                                                • Underlying Diseases in DIC Patients
                                                                                                                                • Slide Number 36
                                                                                                                                • Slide Number 37
                                                                                                                                • Slide Number 38
                                                                                                                                • Slide Number 39
                                                                                                                                • Pathophysiology of DIC
                                                                                                                                • Pathogenesis of DIC in Sepsis
                                                                                                                                • Host Response in Severe Sepsis
                                                                                                                                • Organ Failure in Severe Sepsis
                                                                                                                                • Mechanism of DIC in Organ Failure
                                                                                                                                • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                • Slide Number 47
                                                                                                                                • Diverse and Opposing Effects of Thrombin
                                                                                                                                • Coagulation and Fibrinolysis in DIC
                                                                                                                                • Mechanism of DIC
                                                                                                                                • Pathophysiology of DIC
                                                                                                                                • Pathophysiology of DIC - Mechanism
                                                                                                                                • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                • Pathophysiology of Overt DIC
                                                                                                                                • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                • Slide Number 57
                                                                                                                                • Slide Number 58
                                                                                                                                • Slide Number 59
                                                                                                                                • Slide Number 60
                                                                                                                                • Slide Number 61
                                                                                                                                • BREAK
                                                                                                                                • Diagnostic and Management Approach for DIC
                                                                                                                                • Diagnosis of DIC
                                                                                                                                • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                • Slide Number 67
                                                                                                                                • Slide Number 68
                                                                                                                                • British Journal of Haematology Overt DIC Score
                                                                                                                                • Slide Number 70
                                                                                                                                • Slide Number 71
                                                                                                                                • Slide Number 72
                                                                                                                                • Slide Number 73
                                                                                                                                • DIC Management Goals
                                                                                                                                • DIC Management and Treatment
                                                                                                                                • DIC Management Strategies
                                                                                                                                • Anticoagulant Factor Concentrate Treatment
                                                                                                                                • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                • D-dimer FDPs and DIC
                                                                                                                                • D-Dimer and FDPs in DIC
                                                                                                                                • Follow Up of DIC State of Disease
                                                                                                                                • FMD-Dimer in DIC Major Differences
                                                                                                                                • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                • Slide Number 85
                                                                                                                                • Slide Number 86
                                                                                                                                • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                • Slide Number 94
                                                                                                                                • Slide Number 95
                                                                                                                                • Slide Number 96
                                                                                                                                • Slide Number 97
                                                                                                                                • Slide Number 98
                                                                                                                                • Slide Number 99
                                                                                                                                • DIC Case Studies
                                                                                                                                • Case Study 1 - Presentation
                                                                                                                                • Case Study 1 ndash Lab Results
                                                                                                                                • Case Study 1 ndash Microscopy
                                                                                                                                • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                • Slide Number 105
                                                                                                                                • Slide Number 106
                                                                                                                                • Slide Number 107
                                                                                                                                • Slide Number 108
                                                                                                                                • Slide Number 109
                                                                                                                                • Slide Number 110
                                                                                                                                • Slide Number 111
                                                                                                                                • Slide Number 112
                                                                                                                                • Slide Number 113
                                                                                                                                • Slide Number 114
                                                                                                                                • Slide Number 115
                                                                                                                                • Slide Number 116
                                                                                                                                • Slide Number 117
                                                                                                                                • Slide Number 118
                                                                                                                                • Slide Number 119
                                                                                                                                • Slide Number 120
                                                                                                                                • Slide Number 121
                                                                                                                                • Slide Number 122
                                                                                                                                • Slide Number 123
                                                                                                                                • Slide Number 124
                                                                                                                                • Slide Number 125
                                                                                                                                • DIC Take Home Messages
                                                                                                                                • Slide Number 127
                                                                                                                                • Slide Number 128

                                                                                                                                  Lab Diagnosis of DIC ndash Markers of Factor Consumption

                                                                                                                                  Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time

                                                                                                                                  Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs

                                                                                                                                  Important to recognize simultaneous formation of thrombin and plasmin

                                                                                                                                  Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                                                                  Lab Diagnosis of DIC ndash Screening Tests

                                                                                                                                  Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                                                                  Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                                                                                                                  fibrinogen level) repeat testing assesses progression

                                                                                                                                  Screening tests not clinically specific or sensitive for DIC

                                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                  Laboratory Changes in Overt DIC

                                                                                                                                  DIC Diagnostic Practices Over Time

                                                                                                                                  Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                  British Journal of Haematology Overt DIC Score

                                                                                                                                  Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                  ISTH Step by Step DIC Algorithm

                                                                                                                                  Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                                                                                                  US Based Validation of ISTH DIC Score

                                                                                                                                  When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                  Differential Diagnosis in DIC

                                                                                                                                  aHUS atypical hemolytic uremic syndrome

                                                                                                                                  HUS hemolytic uremic syndrome

                                                                                                                                  HIT heparin-induced thrombocytopenia

                                                                                                                                  ITP immune thrombocytopenic purpura

                                                                                                                                  TTP thrombotic thrombocytopenic purpura

                                                                                                                                  DIC and MAHA

                                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                  lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                                                                                                  When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                                                                                                  DIC Management Goals

                                                                                                                                  Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                                                  Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                                                                                                  DIC Management and Treatment

                                                                                                                                  Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                                                  Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                                                                                                  requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                                                                                                  Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                                                                                                  DIC Management Strategies

                                                                                                                                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                                  Anticoagulant Factor Concentrate Treatment

                                                                                                                                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                                  Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                                                                                  Anticoagulant Factor Concentrate Treatment Trials

                                                                                                                                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                                  Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                                                                                  Markers of Thrombin amp Plasmin Generation in DIC

                                                                                                                                  D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                                                                                  Cut-off value

                                                                                                                                  Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                                                                                  degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                                                                                  D-dimer FDPs and DIC

                                                                                                                                  D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                                                                                  Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                                                                                  Follow Up of DIC State of Disease

                                                                                                                                  Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                                                                                  Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                                                                                  FMD-Dimer in DIC Major Differences

                                                                                                                                  onset of thrombosis

                                                                                                                                  days

                                                                                                                                  Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                                                                                  FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                                                                                  D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                                                                                  of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                                                                                  0

                                                                                                                                  20

                                                                                                                                  40

                                                                                                                                  60

                                                                                                                                  80

                                                                                                                                  100

                                                                                                                                  94 85 90N = 62

                                                                                                                                  Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                                                                                  Positivity of Test Results ISTH Score and Disease State

                                                                                                                                  Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                  Red bar positive for 2 points of DIC score

                                                                                                                                  Pink bar positive for 1-2 points of DIC score

                                                                                                                                  HT hematopoietic tumor

                                                                                                                                  IF infection

                                                                                                                                  SC solid cancer

                                                                                                                                  Markers in Patients with or without DIC

                                                                                                                                  Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                  HT hematopoietic tumorIF infectionSC solid cancer

                                                                                                                                  Comparing an Automated FM vs Manual FSP Test

                                                                                                                                  Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                                                                  Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                                                                  Automated (Mitsubishi) vs Automated (Stago)

                                                                                                                                  In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                                                                  Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                  In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                  In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                  In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                  Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                  No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                                                  Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                  Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                  Non Overt DIC Overt DIC

                                                                                                                                  AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                                                  Trends in Markers of DIC for Different Patients

                                                                                                                                  Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                                                  Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                                                  Trends in Markers of DIC for Different Patients

                                                                                                                                  Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                  FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                                                  28 day outcome survival

                                                                                                                                  28 day outcome death

                                                                                                                                  Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                  Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                  Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                                                  Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                  Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                  Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                                                  DIC Case Studies

                                                                                                                                  Case Study 1 - Presentation

                                                                                                                                  18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                  Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                                  WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                                  RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                                  Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                                  Hematocrit 195 401 ndash 510

                                                                                                                                  MCV 95 fL 790 ndash 922 fL

                                                                                                                                  MPV 12 fL 94 ndash 124 fL

                                                                                                                                  Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                                  Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                                  Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                                  PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                                  APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                                  Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                                  D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                  Case Study 1 ndash Microscopy

                                                                                                                                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                  Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                                  Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                                  DIC due to TF release by APL blasts

                                                                                                                                  Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                                  Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                  20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                                  Case Study 2 ndash Presentation

                                                                                                                                  TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                                  PT 30 sec 113 ndash 146 sec

                                                                                                                                  APTT 75 sec 25 ndash 34 sec

                                                                                                                                  D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                                  Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                                  pH 728 738 to 742

                                                                                                                                  PaO2 570 mmHg 80-100 mmHg

                                                                                                                                  WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                                  ALT 111 IUL 0ndash34 IUL

                                                                                                                                  AST 61 IUL 0ndash34 IUL

                                                                                                                                  BUN 303 mgdL 08-13 mgdL

                                                                                                                                  Case Study 2 ndash Lab Results

                                                                                                                                  Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                                  Case Study 2 ndash Diagnosis

                                                                                                                                  60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                                  Case Study 3 ndash Presentation

                                                                                                                                  TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                  PT 228 sec 113 ndash 146 sec

                                                                                                                                  APTT 45 sec 25 ndash 34 sec

                                                                                                                                  D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                  Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                  FV Normal 70-120

                                                                                                                                  FVII Normal 55-170

                                                                                                                                  FVIII Normal 60-150

                                                                                                                                  Protein C Normal 70-130

                                                                                                                                  Hb 134 gdL 14-16 gdL

                                                                                                                                  WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                  ALT 32 IUL 0ndash34 IUL

                                                                                                                                  AST 28 IUL 0ndash34 IUL

                                                                                                                                  BUN 09 mgdL 08-13 mgdL

                                                                                                                                  Case Study 3 ndash Lab Results

                                                                                                                                  Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                  Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                  Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                  Case Study 4 ndash Presentation

                                                                                                                                  TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                  PT 28 sec 113 ndash 146 sec

                                                                                                                                  APTT 71 sec 25 ndash 34 sec

                                                                                                                                  D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                  Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                  FV Normal 70-120

                                                                                                                                  FVII Normal 55-170

                                                                                                                                  FVIII Normal 60-150

                                                                                                                                  Protein C Normal 70-130

                                                                                                                                  Hb 158 gdL 14-16 gdL

                                                                                                                                  WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                  ALT 60 IUL 0ndash34 IUL

                                                                                                                                  AST 47 IUL 0ndash34 IUL

                                                                                                                                  BUN 38 mgdL 08-13 mgdL

                                                                                                                                  Case Study 4 ndash Lab Results

                                                                                                                                  Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                  Case Study 4 ndash Diagnosis

                                                                                                                                  55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                  Case Study 5 ndash Presentation

                                                                                                                                  Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                  Case Study 5 ndash Lab Results and Time Course

                                                                                                                                  Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                  TEST RESULT REFERENCE RANGE

                                                                                                                                  Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                  PT 215 sec 103 ndash 128 sec

                                                                                                                                  APTT 44 sec 26 ndash 36 sec

                                                                                                                                  D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                  Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                  FII FV FVIII Low Not reported (NR)

                                                                                                                                  FVII FIX FX vWF Normal NR

                                                                                                                                  Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                  DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                  dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                  (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                  (D) Illustration demonstrating repair

                                                                                                                                  Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                  Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                  29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                  Case Study 6 ndash Presentation

                                                                                                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                  Case Study 6 ndash Lab Results

                                                                                                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                  TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                  PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                  INR 658 1 ndash 125

                                                                                                                                  APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                  D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                  Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                  Albumin 28 gdL NR

                                                                                                                                  Hb 58 gdL NR

                                                                                                                                  LDH 1196 UL NR

                                                                                                                                  SGPT 144 IU NR

                                                                                                                                  SGOT 88 IU NR

                                                                                                                                  Bilirubin 32 mgdL NR

                                                                                                                                  DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                  day postop

                                                                                                                                  Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                  HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                  Case Study 6 ndash Discussion

                                                                                                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                  44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                  Case Study 7 ndash Presentation

                                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                  On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                  Case Study 7 ndash Presentation

                                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                  Case Study 7 ndash Lab Results vs Time

                                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                  Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                  Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                  On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                  Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                  DIC Take Home Messages

                                                                                                                                  Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                  Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                  DIC

                                                                                                                                  Thank you Questions

                                                                                                                                  • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                  • Learning Objectives
                                                                                                                                  • Slide Number 3
                                                                                                                                  • Slide Number 4
                                                                                                                                  • Slide Number 5
                                                                                                                                  • Slide Number 6
                                                                                                                                  • Slide Number 7
                                                                                                                                  • Slide Number 8
                                                                                                                                  • Wound Sealing
                                                                                                                                  • The Three Steps of Hemostasis
                                                                                                                                  • Vessel Wall
                                                                                                                                  • Slide Number 12
                                                                                                                                  • Slide Number 13
                                                                                                                                  • Platelet Structure UnactivatedActivated
                                                                                                                                  • Primary Hemostasis
                                                                                                                                  • Primary Hemostasis Assays
                                                                                                                                  • Slide Number 17
                                                                                                                                  • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                  • Slide Number 19
                                                                                                                                  • Coagulation factors
                                                                                                                                  • Coagulation Assay Mechanisms
                                                                                                                                  • Slide Number 22
                                                                                                                                  • Fibrin Formation
                                                                                                                                  • Slide Number 24
                                                                                                                                  • Fibrinolysis Overview
                                                                                                                                  • Fibrinolysis Overview
                                                                                                                                  • Slide Number 27
                                                                                                                                  • Fibrinolysis Releases D-dimers
                                                                                                                                  • Basic Pathophysiology of DIC
                                                                                                                                  • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                  • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                  • Clinical Conditions Associated With DIC
                                                                                                                                  • Frequency of DIC in Selected Disease States
                                                                                                                                  • Underlying Diseases in DIC Patients
                                                                                                                                  • Slide Number 36
                                                                                                                                  • Slide Number 37
                                                                                                                                  • Slide Number 38
                                                                                                                                  • Slide Number 39
                                                                                                                                  • Pathophysiology of DIC
                                                                                                                                  • Pathogenesis of DIC in Sepsis
                                                                                                                                  • Host Response in Severe Sepsis
                                                                                                                                  • Organ Failure in Severe Sepsis
                                                                                                                                  • Mechanism of DIC in Organ Failure
                                                                                                                                  • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                  • Slide Number 47
                                                                                                                                  • Diverse and Opposing Effects of Thrombin
                                                                                                                                  • Coagulation and Fibrinolysis in DIC
                                                                                                                                  • Mechanism of DIC
                                                                                                                                  • Pathophysiology of DIC
                                                                                                                                  • Pathophysiology of DIC - Mechanism
                                                                                                                                  • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                  • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                  • Pathophysiology of Overt DIC
                                                                                                                                  • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                  • Slide Number 57
                                                                                                                                  • Slide Number 58
                                                                                                                                  • Slide Number 59
                                                                                                                                  • Slide Number 60
                                                                                                                                  • Slide Number 61
                                                                                                                                  • BREAK
                                                                                                                                  • Diagnostic and Management Approach for DIC
                                                                                                                                  • Diagnosis of DIC
                                                                                                                                  • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                  • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                  • Slide Number 67
                                                                                                                                  • Slide Number 68
                                                                                                                                  • British Journal of Haematology Overt DIC Score
                                                                                                                                  • Slide Number 70
                                                                                                                                  • Slide Number 71
                                                                                                                                  • Slide Number 72
                                                                                                                                  • Slide Number 73
                                                                                                                                  • DIC Management Goals
                                                                                                                                  • DIC Management and Treatment
                                                                                                                                  • DIC Management Strategies
                                                                                                                                  • Anticoagulant Factor Concentrate Treatment
                                                                                                                                  • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                  • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                  • D-dimer FDPs and DIC
                                                                                                                                  • D-Dimer and FDPs in DIC
                                                                                                                                  • Follow Up of DIC State of Disease
                                                                                                                                  • FMD-Dimer in DIC Major Differences
                                                                                                                                  • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                  • Slide Number 85
                                                                                                                                  • Slide Number 86
                                                                                                                                  • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                  • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                  • Slide Number 94
                                                                                                                                  • Slide Number 95
                                                                                                                                  • Slide Number 96
                                                                                                                                  • Slide Number 97
                                                                                                                                  • Slide Number 98
                                                                                                                                  • Slide Number 99
                                                                                                                                  • DIC Case Studies
                                                                                                                                  • Case Study 1 - Presentation
                                                                                                                                  • Case Study 1 ndash Lab Results
                                                                                                                                  • Case Study 1 ndash Microscopy
                                                                                                                                  • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                  • Slide Number 105
                                                                                                                                  • Slide Number 106
                                                                                                                                  • Slide Number 107
                                                                                                                                  • Slide Number 108
                                                                                                                                  • Slide Number 109
                                                                                                                                  • Slide Number 110
                                                                                                                                  • Slide Number 111
                                                                                                                                  • Slide Number 112
                                                                                                                                  • Slide Number 113
                                                                                                                                  • Slide Number 114
                                                                                                                                  • Slide Number 115
                                                                                                                                  • Slide Number 116
                                                                                                                                  • Slide Number 117
                                                                                                                                  • Slide Number 118
                                                                                                                                  • Slide Number 119
                                                                                                                                  • Slide Number 120
                                                                                                                                  • Slide Number 121
                                                                                                                                  • Slide Number 122
                                                                                                                                  • Slide Number 123
                                                                                                                                  • Slide Number 124
                                                                                                                                  • Slide Number 125
                                                                                                                                  • DIC Take Home Messages
                                                                                                                                  • Slide Number 127
                                                                                                                                  • Slide Number 128

                                                                                                                                    Lab Diagnosis of DIC ndash Screening Tests

                                                                                                                                    Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122

                                                                                                                                    Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high

                                                                                                                                    fibrinogen level) repeat testing assesses progression

                                                                                                                                    Screening tests not clinically specific or sensitive for DIC

                                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                    Laboratory Changes in Overt DIC

                                                                                                                                    DIC Diagnostic Practices Over Time

                                                                                                                                    Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                    British Journal of Haematology Overt DIC Score

                                                                                                                                    Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                    ISTH Step by Step DIC Algorithm

                                                                                                                                    Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                                                                                                    US Based Validation of ISTH DIC Score

                                                                                                                                    When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                    Differential Diagnosis in DIC

                                                                                                                                    aHUS atypical hemolytic uremic syndrome

                                                                                                                                    HUS hemolytic uremic syndrome

                                                                                                                                    HIT heparin-induced thrombocytopenia

                                                                                                                                    ITP immune thrombocytopenic purpura

                                                                                                                                    TTP thrombotic thrombocytopenic purpura

                                                                                                                                    DIC and MAHA

                                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                    lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                                                                                                    When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                                                                                                    DIC Management Goals

                                                                                                                                    Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                                                    Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                                                                                                    DIC Management and Treatment

                                                                                                                                    Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                                                    Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                                                                                                    requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                                                                                                    Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                                                                                                    DIC Management Strategies

                                                                                                                                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                                    Anticoagulant Factor Concentrate Treatment

                                                                                                                                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                                    Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                                                                                    Anticoagulant Factor Concentrate Treatment Trials

                                                                                                                                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                                    Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                                                                                    Markers of Thrombin amp Plasmin Generation in DIC

                                                                                                                                    D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                                                                                    Cut-off value

                                                                                                                                    Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                                                                                    degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                                                                                    D-dimer FDPs and DIC

                                                                                                                                    D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                                                                                    Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                                                                                    Follow Up of DIC State of Disease

                                                                                                                                    Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                                                                                    Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                                                                                    FMD-Dimer in DIC Major Differences

                                                                                                                                    onset of thrombosis

                                                                                                                                    days

                                                                                                                                    Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                                                                                    FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                                                                                    D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                                                                                    of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                                                                                    0

                                                                                                                                    20

                                                                                                                                    40

                                                                                                                                    60

                                                                                                                                    80

                                                                                                                                    100

                                                                                                                                    94 85 90N = 62

                                                                                                                                    Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                                                                                    Positivity of Test Results ISTH Score and Disease State

                                                                                                                                    Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                    Red bar positive for 2 points of DIC score

                                                                                                                                    Pink bar positive for 1-2 points of DIC score

                                                                                                                                    HT hematopoietic tumor

                                                                                                                                    IF infection

                                                                                                                                    SC solid cancer

                                                                                                                                    Markers in Patients with or without DIC

                                                                                                                                    Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                    HT hematopoietic tumorIF infectionSC solid cancer

                                                                                                                                    Comparing an Automated FM vs Manual FSP Test

                                                                                                                                    Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                                                                    Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                                                                    Automated (Mitsubishi) vs Automated (Stago)

                                                                                                                                    In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                                                                    Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                    In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                    In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                    In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                    Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                    No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                                                    Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                    Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                    Non Overt DIC Overt DIC

                                                                                                                                    AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                                                    Trends in Markers of DIC for Different Patients

                                                                                                                                    Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                                                    Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                                                    Trends in Markers of DIC for Different Patients

                                                                                                                                    Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                    FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                                                    28 day outcome survival

                                                                                                                                    28 day outcome death

                                                                                                                                    Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                    Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                    Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                                                    Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                    Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                    Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                                                    DIC Case Studies

                                                                                                                                    Case Study 1 - Presentation

                                                                                                                                    18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                    Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                                    WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                                    RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                                    Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                                    Hematocrit 195 401 ndash 510

                                                                                                                                    MCV 95 fL 790 ndash 922 fL

                                                                                                                                    MPV 12 fL 94 ndash 124 fL

                                                                                                                                    Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                                    Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                                    Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                                    PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                                    APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                                    Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                                    D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                    Case Study 1 ndash Microscopy

                                                                                                                                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                    Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                                    Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                                    DIC due to TF release by APL blasts

                                                                                                                                    Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                                    Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                    20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                                    Case Study 2 ndash Presentation

                                                                                                                                    TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                                    PT 30 sec 113 ndash 146 sec

                                                                                                                                    APTT 75 sec 25 ndash 34 sec

                                                                                                                                    D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                                    Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                                    pH 728 738 to 742

                                                                                                                                    PaO2 570 mmHg 80-100 mmHg

                                                                                                                                    WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                                    ALT 111 IUL 0ndash34 IUL

                                                                                                                                    AST 61 IUL 0ndash34 IUL

                                                                                                                                    BUN 303 mgdL 08-13 mgdL

                                                                                                                                    Case Study 2 ndash Lab Results

                                                                                                                                    Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                                    Case Study 2 ndash Diagnosis

                                                                                                                                    60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                                    Case Study 3 ndash Presentation

                                                                                                                                    TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                    PT 228 sec 113 ndash 146 sec

                                                                                                                                    APTT 45 sec 25 ndash 34 sec

                                                                                                                                    D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                    Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                    FV Normal 70-120

                                                                                                                                    FVII Normal 55-170

                                                                                                                                    FVIII Normal 60-150

                                                                                                                                    Protein C Normal 70-130

                                                                                                                                    Hb 134 gdL 14-16 gdL

                                                                                                                                    WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                    ALT 32 IUL 0ndash34 IUL

                                                                                                                                    AST 28 IUL 0ndash34 IUL

                                                                                                                                    BUN 09 mgdL 08-13 mgdL

                                                                                                                                    Case Study 3 ndash Lab Results

                                                                                                                                    Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                    Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                    Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                    Case Study 4 ndash Presentation

                                                                                                                                    TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                    PT 28 sec 113 ndash 146 sec

                                                                                                                                    APTT 71 sec 25 ndash 34 sec

                                                                                                                                    D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                    Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                    FV Normal 70-120

                                                                                                                                    FVII Normal 55-170

                                                                                                                                    FVIII Normal 60-150

                                                                                                                                    Protein C Normal 70-130

                                                                                                                                    Hb 158 gdL 14-16 gdL

                                                                                                                                    WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                    ALT 60 IUL 0ndash34 IUL

                                                                                                                                    AST 47 IUL 0ndash34 IUL

                                                                                                                                    BUN 38 mgdL 08-13 mgdL

                                                                                                                                    Case Study 4 ndash Lab Results

                                                                                                                                    Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                    Case Study 4 ndash Diagnosis

                                                                                                                                    55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                    Case Study 5 ndash Presentation

                                                                                                                                    Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                    Case Study 5 ndash Lab Results and Time Course

                                                                                                                                    Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                    TEST RESULT REFERENCE RANGE

                                                                                                                                    Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                    PT 215 sec 103 ndash 128 sec

                                                                                                                                    APTT 44 sec 26 ndash 36 sec

                                                                                                                                    D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                    Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                    FII FV FVIII Low Not reported (NR)

                                                                                                                                    FVII FIX FX vWF Normal NR

                                                                                                                                    Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                    DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                    dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                    (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                    (D) Illustration demonstrating repair

                                                                                                                                    Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                    Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                    29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                    Case Study 6 ndash Presentation

                                                                                                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                    Case Study 6 ndash Lab Results

                                                                                                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                    TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                    PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                    INR 658 1 ndash 125

                                                                                                                                    APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                    D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                    Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                    Albumin 28 gdL NR

                                                                                                                                    Hb 58 gdL NR

                                                                                                                                    LDH 1196 UL NR

                                                                                                                                    SGPT 144 IU NR

                                                                                                                                    SGOT 88 IU NR

                                                                                                                                    Bilirubin 32 mgdL NR

                                                                                                                                    DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                    day postop

                                                                                                                                    Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                    HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                    Case Study 6 ndash Discussion

                                                                                                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                    44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                    Case Study 7 ndash Presentation

                                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                    On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                    Case Study 7 ndash Presentation

                                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                    Case Study 7 ndash Lab Results vs Time

                                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                    Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                    Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                    On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                    Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                    DIC Take Home Messages

                                                                                                                                    Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                    Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                    DIC

                                                                                                                                    Thank you Questions

                                                                                                                                    • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                    • Learning Objectives
                                                                                                                                    • Slide Number 3
                                                                                                                                    • Slide Number 4
                                                                                                                                    • Slide Number 5
                                                                                                                                    • Slide Number 6
                                                                                                                                    • Slide Number 7
                                                                                                                                    • Slide Number 8
                                                                                                                                    • Wound Sealing
                                                                                                                                    • The Three Steps of Hemostasis
                                                                                                                                    • Vessel Wall
                                                                                                                                    • Slide Number 12
                                                                                                                                    • Slide Number 13
                                                                                                                                    • Platelet Structure UnactivatedActivated
                                                                                                                                    • Primary Hemostasis
                                                                                                                                    • Primary Hemostasis Assays
                                                                                                                                    • Slide Number 17
                                                                                                                                    • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                    • Slide Number 19
                                                                                                                                    • Coagulation factors
                                                                                                                                    • Coagulation Assay Mechanisms
                                                                                                                                    • Slide Number 22
                                                                                                                                    • Fibrin Formation
                                                                                                                                    • Slide Number 24
                                                                                                                                    • Fibrinolysis Overview
                                                                                                                                    • Fibrinolysis Overview
                                                                                                                                    • Slide Number 27
                                                                                                                                    • Fibrinolysis Releases D-dimers
                                                                                                                                    • Basic Pathophysiology of DIC
                                                                                                                                    • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                    • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                    • Clinical Conditions Associated With DIC
                                                                                                                                    • Frequency of DIC in Selected Disease States
                                                                                                                                    • Underlying Diseases in DIC Patients
                                                                                                                                    • Slide Number 36
                                                                                                                                    • Slide Number 37
                                                                                                                                    • Slide Number 38
                                                                                                                                    • Slide Number 39
                                                                                                                                    • Pathophysiology of DIC
                                                                                                                                    • Pathogenesis of DIC in Sepsis
                                                                                                                                    • Host Response in Severe Sepsis
                                                                                                                                    • Organ Failure in Severe Sepsis
                                                                                                                                    • Mechanism of DIC in Organ Failure
                                                                                                                                    • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                    • Slide Number 47
                                                                                                                                    • Diverse and Opposing Effects of Thrombin
                                                                                                                                    • Coagulation and Fibrinolysis in DIC
                                                                                                                                    • Mechanism of DIC
                                                                                                                                    • Pathophysiology of DIC
                                                                                                                                    • Pathophysiology of DIC - Mechanism
                                                                                                                                    • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                    • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                    • Pathophysiology of Overt DIC
                                                                                                                                    • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                    • Slide Number 57
                                                                                                                                    • Slide Number 58
                                                                                                                                    • Slide Number 59
                                                                                                                                    • Slide Number 60
                                                                                                                                    • Slide Number 61
                                                                                                                                    • BREAK
                                                                                                                                    • Diagnostic and Management Approach for DIC
                                                                                                                                    • Diagnosis of DIC
                                                                                                                                    • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                    • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                    • Slide Number 67
                                                                                                                                    • Slide Number 68
                                                                                                                                    • British Journal of Haematology Overt DIC Score
                                                                                                                                    • Slide Number 70
                                                                                                                                    • Slide Number 71
                                                                                                                                    • Slide Number 72
                                                                                                                                    • Slide Number 73
                                                                                                                                    • DIC Management Goals
                                                                                                                                    • DIC Management and Treatment
                                                                                                                                    • DIC Management Strategies
                                                                                                                                    • Anticoagulant Factor Concentrate Treatment
                                                                                                                                    • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                    • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                    • D-dimer FDPs and DIC
                                                                                                                                    • D-Dimer and FDPs in DIC
                                                                                                                                    • Follow Up of DIC State of Disease
                                                                                                                                    • FMD-Dimer in DIC Major Differences
                                                                                                                                    • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                    • Slide Number 85
                                                                                                                                    • Slide Number 86
                                                                                                                                    • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                    • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                    • Slide Number 94
                                                                                                                                    • Slide Number 95
                                                                                                                                    • Slide Number 96
                                                                                                                                    • Slide Number 97
                                                                                                                                    • Slide Number 98
                                                                                                                                    • Slide Number 99
                                                                                                                                    • DIC Case Studies
                                                                                                                                    • Case Study 1 - Presentation
                                                                                                                                    • Case Study 1 ndash Lab Results
                                                                                                                                    • Case Study 1 ndash Microscopy
                                                                                                                                    • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                    • Slide Number 105
                                                                                                                                    • Slide Number 106
                                                                                                                                    • Slide Number 107
                                                                                                                                    • Slide Number 108
                                                                                                                                    • Slide Number 109
                                                                                                                                    • Slide Number 110
                                                                                                                                    • Slide Number 111
                                                                                                                                    • Slide Number 112
                                                                                                                                    • Slide Number 113
                                                                                                                                    • Slide Number 114
                                                                                                                                    • Slide Number 115
                                                                                                                                    • Slide Number 116
                                                                                                                                    • Slide Number 117
                                                                                                                                    • Slide Number 118
                                                                                                                                    • Slide Number 119
                                                                                                                                    • Slide Number 120
                                                                                                                                    • Slide Number 121
                                                                                                                                    • Slide Number 122
                                                                                                                                    • Slide Number 123
                                                                                                                                    • Slide Number 124
                                                                                                                                    • Slide Number 125
                                                                                                                                    • DIC Take Home Messages
                                                                                                                                    • Slide Number 127
                                                                                                                                    • Slide Number 128

                                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                      Laboratory Changes in Overt DIC

                                                                                                                                      DIC Diagnostic Practices Over Time

                                                                                                                                      Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                      British Journal of Haematology Overt DIC Score

                                                                                                                                      Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                      ISTH Step by Step DIC Algorithm

                                                                                                                                      Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                                                                                                      US Based Validation of ISTH DIC Score

                                                                                                                                      When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                      Differential Diagnosis in DIC

                                                                                                                                      aHUS atypical hemolytic uremic syndrome

                                                                                                                                      HUS hemolytic uremic syndrome

                                                                                                                                      HIT heparin-induced thrombocytopenia

                                                                                                                                      ITP immune thrombocytopenic purpura

                                                                                                                                      TTP thrombotic thrombocytopenic purpura

                                                                                                                                      DIC and MAHA

                                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                      lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                                                                                                      When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                                                                                                      DIC Management Goals

                                                                                                                                      Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                                                      Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                                                                                                      DIC Management and Treatment

                                                                                                                                      Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                                                      Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                                                                                                      requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                                                                                                      Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                                                                                                      DIC Management Strategies

                                                                                                                                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                                      Anticoagulant Factor Concentrate Treatment

                                                                                                                                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                                      Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                                                                                      Anticoagulant Factor Concentrate Treatment Trials

                                                                                                                                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                                      Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                                                                                      Markers of Thrombin amp Plasmin Generation in DIC

                                                                                                                                      D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                                                                                      Cut-off value

                                                                                                                                      Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                                                                                      degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                                                                                      D-dimer FDPs and DIC

                                                                                                                                      D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                                                                                      Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                                                                                      Follow Up of DIC State of Disease

                                                                                                                                      Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                                                                                      Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                                                                                      FMD-Dimer in DIC Major Differences

                                                                                                                                      onset of thrombosis

                                                                                                                                      days

                                                                                                                                      Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                                                                                      FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                                                                                      D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                                                                                      of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                                                                                      0

                                                                                                                                      20

                                                                                                                                      40

                                                                                                                                      60

                                                                                                                                      80

                                                                                                                                      100

                                                                                                                                      94 85 90N = 62

                                                                                                                                      Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                                                                                      Positivity of Test Results ISTH Score and Disease State

                                                                                                                                      Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                      Red bar positive for 2 points of DIC score

                                                                                                                                      Pink bar positive for 1-2 points of DIC score

                                                                                                                                      HT hematopoietic tumor

                                                                                                                                      IF infection

                                                                                                                                      SC solid cancer

                                                                                                                                      Markers in Patients with or without DIC

                                                                                                                                      Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                      HT hematopoietic tumorIF infectionSC solid cancer

                                                                                                                                      Comparing an Automated FM vs Manual FSP Test

                                                                                                                                      Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                                                                      Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                                                                      Automated (Mitsubishi) vs Automated (Stago)

                                                                                                                                      In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                                                                      Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                      In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                      In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                      In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                      Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                      No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                                                      Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                      Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                      Non Overt DIC Overt DIC

                                                                                                                                      AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                                                      Trends in Markers of DIC for Different Patients

                                                                                                                                      Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                                                      Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                                                      Trends in Markers of DIC for Different Patients

                                                                                                                                      Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                      FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                                                      28 day outcome survival

                                                                                                                                      28 day outcome death

                                                                                                                                      Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                      Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                      Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                                                      Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                      Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                      Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                                                      DIC Case Studies

                                                                                                                                      Case Study 1 - Presentation

                                                                                                                                      18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                      Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                                      WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                                      RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                                      Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                                      Hematocrit 195 401 ndash 510

                                                                                                                                      MCV 95 fL 790 ndash 922 fL

                                                                                                                                      MPV 12 fL 94 ndash 124 fL

                                                                                                                                      Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                                      Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                                      Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                                      PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                                      APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                                      Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                                      D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                      Case Study 1 ndash Microscopy

                                                                                                                                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                      Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                                      Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                                      DIC due to TF release by APL blasts

                                                                                                                                      Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                                      Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                      20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                                      Case Study 2 ndash Presentation

                                                                                                                                      TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                                      PT 30 sec 113 ndash 146 sec

                                                                                                                                      APTT 75 sec 25 ndash 34 sec

                                                                                                                                      D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                                      Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                                      pH 728 738 to 742

                                                                                                                                      PaO2 570 mmHg 80-100 mmHg

                                                                                                                                      WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                                      ALT 111 IUL 0ndash34 IUL

                                                                                                                                      AST 61 IUL 0ndash34 IUL

                                                                                                                                      BUN 303 mgdL 08-13 mgdL

                                                                                                                                      Case Study 2 ndash Lab Results

                                                                                                                                      Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                                      Case Study 2 ndash Diagnosis

                                                                                                                                      60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                                      Case Study 3 ndash Presentation

                                                                                                                                      TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                      PT 228 sec 113 ndash 146 sec

                                                                                                                                      APTT 45 sec 25 ndash 34 sec

                                                                                                                                      D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                      Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                      FV Normal 70-120

                                                                                                                                      FVII Normal 55-170

                                                                                                                                      FVIII Normal 60-150

                                                                                                                                      Protein C Normal 70-130

                                                                                                                                      Hb 134 gdL 14-16 gdL

                                                                                                                                      WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                      ALT 32 IUL 0ndash34 IUL

                                                                                                                                      AST 28 IUL 0ndash34 IUL

                                                                                                                                      BUN 09 mgdL 08-13 mgdL

                                                                                                                                      Case Study 3 ndash Lab Results

                                                                                                                                      Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                      Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                      Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                      Case Study 4 ndash Presentation

                                                                                                                                      TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                      PT 28 sec 113 ndash 146 sec

                                                                                                                                      APTT 71 sec 25 ndash 34 sec

                                                                                                                                      D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                      Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                      FV Normal 70-120

                                                                                                                                      FVII Normal 55-170

                                                                                                                                      FVIII Normal 60-150

                                                                                                                                      Protein C Normal 70-130

                                                                                                                                      Hb 158 gdL 14-16 gdL

                                                                                                                                      WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                      ALT 60 IUL 0ndash34 IUL

                                                                                                                                      AST 47 IUL 0ndash34 IUL

                                                                                                                                      BUN 38 mgdL 08-13 mgdL

                                                                                                                                      Case Study 4 ndash Lab Results

                                                                                                                                      Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                      Case Study 4 ndash Diagnosis

                                                                                                                                      55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                      Case Study 5 ndash Presentation

                                                                                                                                      Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                      Case Study 5 ndash Lab Results and Time Course

                                                                                                                                      Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                      TEST RESULT REFERENCE RANGE

                                                                                                                                      Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                      PT 215 sec 103 ndash 128 sec

                                                                                                                                      APTT 44 sec 26 ndash 36 sec

                                                                                                                                      D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                      Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                      FII FV FVIII Low Not reported (NR)

                                                                                                                                      FVII FIX FX vWF Normal NR

                                                                                                                                      Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                      DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                      dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                      (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                      (D) Illustration demonstrating repair

                                                                                                                                      Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                      Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                      29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                      Case Study 6 ndash Presentation

                                                                                                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                      Case Study 6 ndash Lab Results

                                                                                                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                      TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                      PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                      INR 658 1 ndash 125

                                                                                                                                      APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                      D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                      Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                      Albumin 28 gdL NR

                                                                                                                                      Hb 58 gdL NR

                                                                                                                                      LDH 1196 UL NR

                                                                                                                                      SGPT 144 IU NR

                                                                                                                                      SGOT 88 IU NR

                                                                                                                                      Bilirubin 32 mgdL NR

                                                                                                                                      DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                      day postop

                                                                                                                                      Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                      HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                      Case Study 6 ndash Discussion

                                                                                                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                      44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                      Case Study 7 ndash Presentation

                                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                      On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                      Case Study 7 ndash Presentation

                                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                      Case Study 7 ndash Lab Results vs Time

                                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                      Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                      Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                      On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                      Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                      DIC Take Home Messages

                                                                                                                                      Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                      Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                      DIC

                                                                                                                                      Thank you Questions

                                                                                                                                      • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                      • Learning Objectives
                                                                                                                                      • Slide Number 3
                                                                                                                                      • Slide Number 4
                                                                                                                                      • Slide Number 5
                                                                                                                                      • Slide Number 6
                                                                                                                                      • Slide Number 7
                                                                                                                                      • Slide Number 8
                                                                                                                                      • Wound Sealing
                                                                                                                                      • The Three Steps of Hemostasis
                                                                                                                                      • Vessel Wall
                                                                                                                                      • Slide Number 12
                                                                                                                                      • Slide Number 13
                                                                                                                                      • Platelet Structure UnactivatedActivated
                                                                                                                                      • Primary Hemostasis
                                                                                                                                      • Primary Hemostasis Assays
                                                                                                                                      • Slide Number 17
                                                                                                                                      • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                      • Slide Number 19
                                                                                                                                      • Coagulation factors
                                                                                                                                      • Coagulation Assay Mechanisms
                                                                                                                                      • Slide Number 22
                                                                                                                                      • Fibrin Formation
                                                                                                                                      • Slide Number 24
                                                                                                                                      • Fibrinolysis Overview
                                                                                                                                      • Fibrinolysis Overview
                                                                                                                                      • Slide Number 27
                                                                                                                                      • Fibrinolysis Releases D-dimers
                                                                                                                                      • Basic Pathophysiology of DIC
                                                                                                                                      • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                      • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                      • Clinical Conditions Associated With DIC
                                                                                                                                      • Frequency of DIC in Selected Disease States
                                                                                                                                      • Underlying Diseases in DIC Patients
                                                                                                                                      • Slide Number 36
                                                                                                                                      • Slide Number 37
                                                                                                                                      • Slide Number 38
                                                                                                                                      • Slide Number 39
                                                                                                                                      • Pathophysiology of DIC
                                                                                                                                      • Pathogenesis of DIC in Sepsis
                                                                                                                                      • Host Response in Severe Sepsis
                                                                                                                                      • Organ Failure in Severe Sepsis
                                                                                                                                      • Mechanism of DIC in Organ Failure
                                                                                                                                      • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                      • Slide Number 47
                                                                                                                                      • Diverse and Opposing Effects of Thrombin
                                                                                                                                      • Coagulation and Fibrinolysis in DIC
                                                                                                                                      • Mechanism of DIC
                                                                                                                                      • Pathophysiology of DIC
                                                                                                                                      • Pathophysiology of DIC - Mechanism
                                                                                                                                      • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                      • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                      • Pathophysiology of Overt DIC
                                                                                                                                      • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                      • Slide Number 57
                                                                                                                                      • Slide Number 58
                                                                                                                                      • Slide Number 59
                                                                                                                                      • Slide Number 60
                                                                                                                                      • Slide Number 61
                                                                                                                                      • BREAK
                                                                                                                                      • Diagnostic and Management Approach for DIC
                                                                                                                                      • Diagnosis of DIC
                                                                                                                                      • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                      • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                      • Slide Number 67
                                                                                                                                      • Slide Number 68
                                                                                                                                      • British Journal of Haematology Overt DIC Score
                                                                                                                                      • Slide Number 70
                                                                                                                                      • Slide Number 71
                                                                                                                                      • Slide Number 72
                                                                                                                                      • Slide Number 73
                                                                                                                                      • DIC Management Goals
                                                                                                                                      • DIC Management and Treatment
                                                                                                                                      • DIC Management Strategies
                                                                                                                                      • Anticoagulant Factor Concentrate Treatment
                                                                                                                                      • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                      • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                      • D-dimer FDPs and DIC
                                                                                                                                      • D-Dimer and FDPs in DIC
                                                                                                                                      • Follow Up of DIC State of Disease
                                                                                                                                      • FMD-Dimer in DIC Major Differences
                                                                                                                                      • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                      • Slide Number 85
                                                                                                                                      • Slide Number 86
                                                                                                                                      • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                      • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                      • Slide Number 94
                                                                                                                                      • Slide Number 95
                                                                                                                                      • Slide Number 96
                                                                                                                                      • Slide Number 97
                                                                                                                                      • Slide Number 98
                                                                                                                                      • Slide Number 99
                                                                                                                                      • DIC Case Studies
                                                                                                                                      • Case Study 1 - Presentation
                                                                                                                                      • Case Study 1 ndash Lab Results
                                                                                                                                      • Case Study 1 ndash Microscopy
                                                                                                                                      • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                      • Slide Number 105
                                                                                                                                      • Slide Number 106
                                                                                                                                      • Slide Number 107
                                                                                                                                      • Slide Number 108
                                                                                                                                      • Slide Number 109
                                                                                                                                      • Slide Number 110
                                                                                                                                      • Slide Number 111
                                                                                                                                      • Slide Number 112
                                                                                                                                      • Slide Number 113
                                                                                                                                      • Slide Number 114
                                                                                                                                      • Slide Number 115
                                                                                                                                      • Slide Number 116
                                                                                                                                      • Slide Number 117
                                                                                                                                      • Slide Number 118
                                                                                                                                      • Slide Number 119
                                                                                                                                      • Slide Number 120
                                                                                                                                      • Slide Number 121
                                                                                                                                      • Slide Number 122
                                                                                                                                      • Slide Number 123
                                                                                                                                      • Slide Number 124
                                                                                                                                      • Slide Number 125
                                                                                                                                      • DIC Take Home Messages
                                                                                                                                      • Slide Number 127
                                                                                                                                      • Slide Number 128

                                                                                                                                        DIC Diagnostic Practices Over Time

                                                                                                                                        Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                        British Journal of Haematology Overt DIC Score

                                                                                                                                        Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                        ISTH Step by Step DIC Algorithm

                                                                                                                                        Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                                                                                                        US Based Validation of ISTH DIC Score

                                                                                                                                        When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                        Differential Diagnosis in DIC

                                                                                                                                        aHUS atypical hemolytic uremic syndrome

                                                                                                                                        HUS hemolytic uremic syndrome

                                                                                                                                        HIT heparin-induced thrombocytopenia

                                                                                                                                        ITP immune thrombocytopenic purpura

                                                                                                                                        TTP thrombotic thrombocytopenic purpura

                                                                                                                                        DIC and MAHA

                                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                        lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                                                                                                        When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                                                                                                        DIC Management Goals

                                                                                                                                        Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                                                        Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                                                                                                        DIC Management and Treatment

                                                                                                                                        Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                                                        Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                                                                                                        requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                                                                                                        Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                                                                                                        DIC Management Strategies

                                                                                                                                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                                        Anticoagulant Factor Concentrate Treatment

                                                                                                                                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                                        Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                                                                                        Anticoagulant Factor Concentrate Treatment Trials

                                                                                                                                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                                        Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                                                                                        Markers of Thrombin amp Plasmin Generation in DIC

                                                                                                                                        D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                                                                                        Cut-off value

                                                                                                                                        Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                                                                                        degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                                                                                        D-dimer FDPs and DIC

                                                                                                                                        D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                                                                                        Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                                                                                        Follow Up of DIC State of Disease

                                                                                                                                        Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                                                                                        Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                                                                                        FMD-Dimer in DIC Major Differences

                                                                                                                                        onset of thrombosis

                                                                                                                                        days

                                                                                                                                        Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                                                                                        FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                                                                                        D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                                                                                        of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                                                                                        0

                                                                                                                                        20

                                                                                                                                        40

                                                                                                                                        60

                                                                                                                                        80

                                                                                                                                        100

                                                                                                                                        94 85 90N = 62

                                                                                                                                        Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                                                                                        Positivity of Test Results ISTH Score and Disease State

                                                                                                                                        Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                        Red bar positive for 2 points of DIC score

                                                                                                                                        Pink bar positive for 1-2 points of DIC score

                                                                                                                                        HT hematopoietic tumor

                                                                                                                                        IF infection

                                                                                                                                        SC solid cancer

                                                                                                                                        Markers in Patients with or without DIC

                                                                                                                                        Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                        HT hematopoietic tumorIF infectionSC solid cancer

                                                                                                                                        Comparing an Automated FM vs Manual FSP Test

                                                                                                                                        Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                                                                        Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                                                                        Automated (Mitsubishi) vs Automated (Stago)

                                                                                                                                        In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                                                                        Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                        In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                        In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                        In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                        Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                        No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                                                        Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                        Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                        Non Overt DIC Overt DIC

                                                                                                                                        AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                                                        Trends in Markers of DIC for Different Patients

                                                                                                                                        Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                                                        Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                                                        Trends in Markers of DIC for Different Patients

                                                                                                                                        Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                        FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                                                        28 day outcome survival

                                                                                                                                        28 day outcome death

                                                                                                                                        Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                        Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                        Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                                                        Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                        Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                        Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                                                        DIC Case Studies

                                                                                                                                        Case Study 1 - Presentation

                                                                                                                                        18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                        Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                                        WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                                        RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                                        Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                                        Hematocrit 195 401 ndash 510

                                                                                                                                        MCV 95 fL 790 ndash 922 fL

                                                                                                                                        MPV 12 fL 94 ndash 124 fL

                                                                                                                                        Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                                        Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                                        Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                                        PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                                        APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                                        Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                                        D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                        Case Study 1 ndash Microscopy

                                                                                                                                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                        Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                                        Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                                        DIC due to TF release by APL blasts

                                                                                                                                        Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                                        Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                        20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                                        Case Study 2 ndash Presentation

                                                                                                                                        TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                                        PT 30 sec 113 ndash 146 sec

                                                                                                                                        APTT 75 sec 25 ndash 34 sec

                                                                                                                                        D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                                        Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                                        pH 728 738 to 742

                                                                                                                                        PaO2 570 mmHg 80-100 mmHg

                                                                                                                                        WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                                        ALT 111 IUL 0ndash34 IUL

                                                                                                                                        AST 61 IUL 0ndash34 IUL

                                                                                                                                        BUN 303 mgdL 08-13 mgdL

                                                                                                                                        Case Study 2 ndash Lab Results

                                                                                                                                        Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                                        Case Study 2 ndash Diagnosis

                                                                                                                                        60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                                        Case Study 3 ndash Presentation

                                                                                                                                        TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                        PT 228 sec 113 ndash 146 sec

                                                                                                                                        APTT 45 sec 25 ndash 34 sec

                                                                                                                                        D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                        Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                        FV Normal 70-120

                                                                                                                                        FVII Normal 55-170

                                                                                                                                        FVIII Normal 60-150

                                                                                                                                        Protein C Normal 70-130

                                                                                                                                        Hb 134 gdL 14-16 gdL

                                                                                                                                        WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                        ALT 32 IUL 0ndash34 IUL

                                                                                                                                        AST 28 IUL 0ndash34 IUL

                                                                                                                                        BUN 09 mgdL 08-13 mgdL

                                                                                                                                        Case Study 3 ndash Lab Results

                                                                                                                                        Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                        Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                        Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                        Case Study 4 ndash Presentation

                                                                                                                                        TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                        PT 28 sec 113 ndash 146 sec

                                                                                                                                        APTT 71 sec 25 ndash 34 sec

                                                                                                                                        D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                        Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                        FV Normal 70-120

                                                                                                                                        FVII Normal 55-170

                                                                                                                                        FVIII Normal 60-150

                                                                                                                                        Protein C Normal 70-130

                                                                                                                                        Hb 158 gdL 14-16 gdL

                                                                                                                                        WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                        ALT 60 IUL 0ndash34 IUL

                                                                                                                                        AST 47 IUL 0ndash34 IUL

                                                                                                                                        BUN 38 mgdL 08-13 mgdL

                                                                                                                                        Case Study 4 ndash Lab Results

                                                                                                                                        Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                        Case Study 4 ndash Diagnosis

                                                                                                                                        55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                        Case Study 5 ndash Presentation

                                                                                                                                        Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                        Case Study 5 ndash Lab Results and Time Course

                                                                                                                                        Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                        TEST RESULT REFERENCE RANGE

                                                                                                                                        Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                        PT 215 sec 103 ndash 128 sec

                                                                                                                                        APTT 44 sec 26 ndash 36 sec

                                                                                                                                        D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                        Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                        FII FV FVIII Low Not reported (NR)

                                                                                                                                        FVII FIX FX vWF Normal NR

                                                                                                                                        Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                        DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                        dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                        (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                        (D) Illustration demonstrating repair

                                                                                                                                        Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                        Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                        29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                        Case Study 6 ndash Presentation

                                                                                                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                        Case Study 6 ndash Lab Results

                                                                                                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                        TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                        PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                        INR 658 1 ndash 125

                                                                                                                                        APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                        D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                        Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                        Albumin 28 gdL NR

                                                                                                                                        Hb 58 gdL NR

                                                                                                                                        LDH 1196 UL NR

                                                                                                                                        SGPT 144 IU NR

                                                                                                                                        SGOT 88 IU NR

                                                                                                                                        Bilirubin 32 mgdL NR

                                                                                                                                        DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                        day postop

                                                                                                                                        Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                        HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                        Case Study 6 ndash Discussion

                                                                                                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                        44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                        Case Study 7 ndash Presentation

                                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                        On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                        Case Study 7 ndash Presentation

                                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                        Case Study 7 ndash Lab Results vs Time

                                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                        Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                        Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                        On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                        Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                        DIC Take Home Messages

                                                                                                                                        Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                        Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                        DIC

                                                                                                                                        Thank you Questions

                                                                                                                                        • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                        • Learning Objectives
                                                                                                                                        • Slide Number 3
                                                                                                                                        • Slide Number 4
                                                                                                                                        • Slide Number 5
                                                                                                                                        • Slide Number 6
                                                                                                                                        • Slide Number 7
                                                                                                                                        • Slide Number 8
                                                                                                                                        • Wound Sealing
                                                                                                                                        • The Three Steps of Hemostasis
                                                                                                                                        • Vessel Wall
                                                                                                                                        • Slide Number 12
                                                                                                                                        • Slide Number 13
                                                                                                                                        • Platelet Structure UnactivatedActivated
                                                                                                                                        • Primary Hemostasis
                                                                                                                                        • Primary Hemostasis Assays
                                                                                                                                        • Slide Number 17
                                                                                                                                        • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                        • Slide Number 19
                                                                                                                                        • Coagulation factors
                                                                                                                                        • Coagulation Assay Mechanisms
                                                                                                                                        • Slide Number 22
                                                                                                                                        • Fibrin Formation
                                                                                                                                        • Slide Number 24
                                                                                                                                        • Fibrinolysis Overview
                                                                                                                                        • Fibrinolysis Overview
                                                                                                                                        • Slide Number 27
                                                                                                                                        • Fibrinolysis Releases D-dimers
                                                                                                                                        • Basic Pathophysiology of DIC
                                                                                                                                        • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                        • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                        • Clinical Conditions Associated With DIC
                                                                                                                                        • Frequency of DIC in Selected Disease States
                                                                                                                                        • Underlying Diseases in DIC Patients
                                                                                                                                        • Slide Number 36
                                                                                                                                        • Slide Number 37
                                                                                                                                        • Slide Number 38
                                                                                                                                        • Slide Number 39
                                                                                                                                        • Pathophysiology of DIC
                                                                                                                                        • Pathogenesis of DIC in Sepsis
                                                                                                                                        • Host Response in Severe Sepsis
                                                                                                                                        • Organ Failure in Severe Sepsis
                                                                                                                                        • Mechanism of DIC in Organ Failure
                                                                                                                                        • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                        • Slide Number 47
                                                                                                                                        • Diverse and Opposing Effects of Thrombin
                                                                                                                                        • Coagulation and Fibrinolysis in DIC
                                                                                                                                        • Mechanism of DIC
                                                                                                                                        • Pathophysiology of DIC
                                                                                                                                        • Pathophysiology of DIC - Mechanism
                                                                                                                                        • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                        • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                        • Pathophysiology of Overt DIC
                                                                                                                                        • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                        • Slide Number 57
                                                                                                                                        • Slide Number 58
                                                                                                                                        • Slide Number 59
                                                                                                                                        • Slide Number 60
                                                                                                                                        • Slide Number 61
                                                                                                                                        • BREAK
                                                                                                                                        • Diagnostic and Management Approach for DIC
                                                                                                                                        • Diagnosis of DIC
                                                                                                                                        • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                        • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                        • Slide Number 67
                                                                                                                                        • Slide Number 68
                                                                                                                                        • British Journal of Haematology Overt DIC Score
                                                                                                                                        • Slide Number 70
                                                                                                                                        • Slide Number 71
                                                                                                                                        • Slide Number 72
                                                                                                                                        • Slide Number 73
                                                                                                                                        • DIC Management Goals
                                                                                                                                        • DIC Management and Treatment
                                                                                                                                        • DIC Management Strategies
                                                                                                                                        • Anticoagulant Factor Concentrate Treatment
                                                                                                                                        • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                        • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                        • D-dimer FDPs and DIC
                                                                                                                                        • D-Dimer and FDPs in DIC
                                                                                                                                        • Follow Up of DIC State of Disease
                                                                                                                                        • FMD-Dimer in DIC Major Differences
                                                                                                                                        • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                        • Slide Number 85
                                                                                                                                        • Slide Number 86
                                                                                                                                        • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                        • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                        • Slide Number 94
                                                                                                                                        • Slide Number 95
                                                                                                                                        • Slide Number 96
                                                                                                                                        • Slide Number 97
                                                                                                                                        • Slide Number 98
                                                                                                                                        • Slide Number 99
                                                                                                                                        • DIC Case Studies
                                                                                                                                        • Case Study 1 - Presentation
                                                                                                                                        • Case Study 1 ndash Lab Results
                                                                                                                                        • Case Study 1 ndash Microscopy
                                                                                                                                        • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                        • Slide Number 105
                                                                                                                                        • Slide Number 106
                                                                                                                                        • Slide Number 107
                                                                                                                                        • Slide Number 108
                                                                                                                                        • Slide Number 109
                                                                                                                                        • Slide Number 110
                                                                                                                                        • Slide Number 111
                                                                                                                                        • Slide Number 112
                                                                                                                                        • Slide Number 113
                                                                                                                                        • Slide Number 114
                                                                                                                                        • Slide Number 115
                                                                                                                                        • Slide Number 116
                                                                                                                                        • Slide Number 117
                                                                                                                                        • Slide Number 118
                                                                                                                                        • Slide Number 119
                                                                                                                                        • Slide Number 120
                                                                                                                                        • Slide Number 121
                                                                                                                                        • Slide Number 122
                                                                                                                                        • Slide Number 123
                                                                                                                                        • Slide Number 124
                                                                                                                                        • Slide Number 125
                                                                                                                                        • DIC Take Home Messages
                                                                                                                                        • Slide Number 127
                                                                                                                                        • Slide Number 128

                                                                                                                                          British Journal of Haematology Overt DIC Score

                                                                                                                                          Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33

                                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                          ISTH Step by Step DIC Algorithm

                                                                                                                                          Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                                                                                                          US Based Validation of ISTH DIC Score

                                                                                                                                          When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                          Differential Diagnosis in DIC

                                                                                                                                          aHUS atypical hemolytic uremic syndrome

                                                                                                                                          HUS hemolytic uremic syndrome

                                                                                                                                          HIT heparin-induced thrombocytopenia

                                                                                                                                          ITP immune thrombocytopenic purpura

                                                                                                                                          TTP thrombotic thrombocytopenic purpura

                                                                                                                                          DIC and MAHA

                                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                          lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                                                                                                          When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                                                                                                          DIC Management Goals

                                                                                                                                          Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                                                          Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                                                                                                          DIC Management and Treatment

                                                                                                                                          Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                                                          Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                                                                                                          requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                                                                                                          Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                                                                                                          DIC Management Strategies

                                                                                                                                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                                          Anticoagulant Factor Concentrate Treatment

                                                                                                                                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                                          Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                                                                                          Anticoagulant Factor Concentrate Treatment Trials

                                                                                                                                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                                          Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                                                                                          Markers of Thrombin amp Plasmin Generation in DIC

                                                                                                                                          D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                                                                                          Cut-off value

                                                                                                                                          Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                                                                                          degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                                                                                          D-dimer FDPs and DIC

                                                                                                                                          D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                                                                                          Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                                                                                          Follow Up of DIC State of Disease

                                                                                                                                          Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                                                                                          Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                                                                                          FMD-Dimer in DIC Major Differences

                                                                                                                                          onset of thrombosis

                                                                                                                                          days

                                                                                                                                          Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                                                                                          FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                                                                                          D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                                                                                          of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                                                                                          0

                                                                                                                                          20

                                                                                                                                          40

                                                                                                                                          60

                                                                                                                                          80

                                                                                                                                          100

                                                                                                                                          94 85 90N = 62

                                                                                                                                          Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                                                                                          Positivity of Test Results ISTH Score and Disease State

                                                                                                                                          Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                          Red bar positive for 2 points of DIC score

                                                                                                                                          Pink bar positive for 1-2 points of DIC score

                                                                                                                                          HT hematopoietic tumor

                                                                                                                                          IF infection

                                                                                                                                          SC solid cancer

                                                                                                                                          Markers in Patients with or without DIC

                                                                                                                                          Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                          HT hematopoietic tumorIF infectionSC solid cancer

                                                                                                                                          Comparing an Automated FM vs Manual FSP Test

                                                                                                                                          Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                                                                          Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                                                                          Automated (Mitsubishi) vs Automated (Stago)

                                                                                                                                          In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                                                                          Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                          In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                          In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                          In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                          Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                          No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                                                          Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                          Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                          Non Overt DIC Overt DIC

                                                                                                                                          AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                                                          Trends in Markers of DIC for Different Patients

                                                                                                                                          Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                                                          Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                                                          Trends in Markers of DIC for Different Patients

                                                                                                                                          Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                          FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                                                          28 day outcome survival

                                                                                                                                          28 day outcome death

                                                                                                                                          Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                          Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                          Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                                                          Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                          Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                          Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                                                          DIC Case Studies

                                                                                                                                          Case Study 1 - Presentation

                                                                                                                                          18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                          Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                                          WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                                          RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                                          Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                                          Hematocrit 195 401 ndash 510

                                                                                                                                          MCV 95 fL 790 ndash 922 fL

                                                                                                                                          MPV 12 fL 94 ndash 124 fL

                                                                                                                                          Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                                          Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                                          Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                                          PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                                          APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                                          Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                                          D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                          Case Study 1 ndash Microscopy

                                                                                                                                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                          Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                                          Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                                          DIC due to TF release by APL blasts

                                                                                                                                          Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                                          Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                          20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                                          Case Study 2 ndash Presentation

                                                                                                                                          TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                                          PT 30 sec 113 ndash 146 sec

                                                                                                                                          APTT 75 sec 25 ndash 34 sec

                                                                                                                                          D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                                          Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                                          pH 728 738 to 742

                                                                                                                                          PaO2 570 mmHg 80-100 mmHg

                                                                                                                                          WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                                          ALT 111 IUL 0ndash34 IUL

                                                                                                                                          AST 61 IUL 0ndash34 IUL

                                                                                                                                          BUN 303 mgdL 08-13 mgdL

                                                                                                                                          Case Study 2 ndash Lab Results

                                                                                                                                          Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                                          Case Study 2 ndash Diagnosis

                                                                                                                                          60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                                          Case Study 3 ndash Presentation

                                                                                                                                          TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                          PT 228 sec 113 ndash 146 sec

                                                                                                                                          APTT 45 sec 25 ndash 34 sec

                                                                                                                                          D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                          Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                          FV Normal 70-120

                                                                                                                                          FVII Normal 55-170

                                                                                                                                          FVIII Normal 60-150

                                                                                                                                          Protein C Normal 70-130

                                                                                                                                          Hb 134 gdL 14-16 gdL

                                                                                                                                          WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                          ALT 32 IUL 0ndash34 IUL

                                                                                                                                          AST 28 IUL 0ndash34 IUL

                                                                                                                                          BUN 09 mgdL 08-13 mgdL

                                                                                                                                          Case Study 3 ndash Lab Results

                                                                                                                                          Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                          Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                          Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                          Case Study 4 ndash Presentation

                                                                                                                                          TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                          PT 28 sec 113 ndash 146 sec

                                                                                                                                          APTT 71 sec 25 ndash 34 sec

                                                                                                                                          D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                          Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                          FV Normal 70-120

                                                                                                                                          FVII Normal 55-170

                                                                                                                                          FVIII Normal 60-150

                                                                                                                                          Protein C Normal 70-130

                                                                                                                                          Hb 158 gdL 14-16 gdL

                                                                                                                                          WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                          ALT 60 IUL 0ndash34 IUL

                                                                                                                                          AST 47 IUL 0ndash34 IUL

                                                                                                                                          BUN 38 mgdL 08-13 mgdL

                                                                                                                                          Case Study 4 ndash Lab Results

                                                                                                                                          Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                          Case Study 4 ndash Diagnosis

                                                                                                                                          55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                          Case Study 5 ndash Presentation

                                                                                                                                          Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                          Case Study 5 ndash Lab Results and Time Course

                                                                                                                                          Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                          TEST RESULT REFERENCE RANGE

                                                                                                                                          Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                          PT 215 sec 103 ndash 128 sec

                                                                                                                                          APTT 44 sec 26 ndash 36 sec

                                                                                                                                          D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                          Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                          FII FV FVIII Low Not reported (NR)

                                                                                                                                          FVII FIX FX vWF Normal NR

                                                                                                                                          Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                          DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                          dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                          (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                          (D) Illustration demonstrating repair

                                                                                                                                          Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                          Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                          29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                          Case Study 6 ndash Presentation

                                                                                                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                          Case Study 6 ndash Lab Results

                                                                                                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                          TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                          PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                          INR 658 1 ndash 125

                                                                                                                                          APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                          D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                          Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                          Albumin 28 gdL NR

                                                                                                                                          Hb 58 gdL NR

                                                                                                                                          LDH 1196 UL NR

                                                                                                                                          SGPT 144 IU NR

                                                                                                                                          SGOT 88 IU NR

                                                                                                                                          Bilirubin 32 mgdL NR

                                                                                                                                          DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                          day postop

                                                                                                                                          Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                          HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                          Case Study 6 ndash Discussion

                                                                                                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                          44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                          Case Study 7 ndash Presentation

                                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                          On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                          Case Study 7 ndash Presentation

                                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                          Case Study 7 ndash Lab Results vs Time

                                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                          Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                          Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                          On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                          Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                          DIC Take Home Messages

                                                                                                                                          Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                          Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                          DIC

                                                                                                                                          Thank you Questions

                                                                                                                                          • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                          • Learning Objectives
                                                                                                                                          • Slide Number 3
                                                                                                                                          • Slide Number 4
                                                                                                                                          • Slide Number 5
                                                                                                                                          • Slide Number 6
                                                                                                                                          • Slide Number 7
                                                                                                                                          • Slide Number 8
                                                                                                                                          • Wound Sealing
                                                                                                                                          • The Three Steps of Hemostasis
                                                                                                                                          • Vessel Wall
                                                                                                                                          • Slide Number 12
                                                                                                                                          • Slide Number 13
                                                                                                                                          • Platelet Structure UnactivatedActivated
                                                                                                                                          • Primary Hemostasis
                                                                                                                                          • Primary Hemostasis Assays
                                                                                                                                          • Slide Number 17
                                                                                                                                          • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                          • Slide Number 19
                                                                                                                                          • Coagulation factors
                                                                                                                                          • Coagulation Assay Mechanisms
                                                                                                                                          • Slide Number 22
                                                                                                                                          • Fibrin Formation
                                                                                                                                          • Slide Number 24
                                                                                                                                          • Fibrinolysis Overview
                                                                                                                                          • Fibrinolysis Overview
                                                                                                                                          • Slide Number 27
                                                                                                                                          • Fibrinolysis Releases D-dimers
                                                                                                                                          • Basic Pathophysiology of DIC
                                                                                                                                          • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                          • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                          • Clinical Conditions Associated With DIC
                                                                                                                                          • Frequency of DIC in Selected Disease States
                                                                                                                                          • Underlying Diseases in DIC Patients
                                                                                                                                          • Slide Number 36
                                                                                                                                          • Slide Number 37
                                                                                                                                          • Slide Number 38
                                                                                                                                          • Slide Number 39
                                                                                                                                          • Pathophysiology of DIC
                                                                                                                                          • Pathogenesis of DIC in Sepsis
                                                                                                                                          • Host Response in Severe Sepsis
                                                                                                                                          • Organ Failure in Severe Sepsis
                                                                                                                                          • Mechanism of DIC in Organ Failure
                                                                                                                                          • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                          • Slide Number 47
                                                                                                                                          • Diverse and Opposing Effects of Thrombin
                                                                                                                                          • Coagulation and Fibrinolysis in DIC
                                                                                                                                          • Mechanism of DIC
                                                                                                                                          • Pathophysiology of DIC
                                                                                                                                          • Pathophysiology of DIC - Mechanism
                                                                                                                                          • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                          • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                          • Pathophysiology of Overt DIC
                                                                                                                                          • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                          • Slide Number 57
                                                                                                                                          • Slide Number 58
                                                                                                                                          • Slide Number 59
                                                                                                                                          • Slide Number 60
                                                                                                                                          • Slide Number 61
                                                                                                                                          • BREAK
                                                                                                                                          • Diagnostic and Management Approach for DIC
                                                                                                                                          • Diagnosis of DIC
                                                                                                                                          • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                          • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                          • Slide Number 67
                                                                                                                                          • Slide Number 68
                                                                                                                                          • British Journal of Haematology Overt DIC Score
                                                                                                                                          • Slide Number 70
                                                                                                                                          • Slide Number 71
                                                                                                                                          • Slide Number 72
                                                                                                                                          • Slide Number 73
                                                                                                                                          • DIC Management Goals
                                                                                                                                          • DIC Management and Treatment
                                                                                                                                          • DIC Management Strategies
                                                                                                                                          • Anticoagulant Factor Concentrate Treatment
                                                                                                                                          • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                          • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                          • D-dimer FDPs and DIC
                                                                                                                                          • D-Dimer and FDPs in DIC
                                                                                                                                          • Follow Up of DIC State of Disease
                                                                                                                                          • FMD-Dimer in DIC Major Differences
                                                                                                                                          • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                          • Slide Number 85
                                                                                                                                          • Slide Number 86
                                                                                                                                          • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                          • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                          • Slide Number 94
                                                                                                                                          • Slide Number 95
                                                                                                                                          • Slide Number 96
                                                                                                                                          • Slide Number 97
                                                                                                                                          • Slide Number 98
                                                                                                                                          • Slide Number 99
                                                                                                                                          • DIC Case Studies
                                                                                                                                          • Case Study 1 - Presentation
                                                                                                                                          • Case Study 1 ndash Lab Results
                                                                                                                                          • Case Study 1 ndash Microscopy
                                                                                                                                          • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                          • Slide Number 105
                                                                                                                                          • Slide Number 106
                                                                                                                                          • Slide Number 107
                                                                                                                                          • Slide Number 108
                                                                                                                                          • Slide Number 109
                                                                                                                                          • Slide Number 110
                                                                                                                                          • Slide Number 111
                                                                                                                                          • Slide Number 112
                                                                                                                                          • Slide Number 113
                                                                                                                                          • Slide Number 114
                                                                                                                                          • Slide Number 115
                                                                                                                                          • Slide Number 116
                                                                                                                                          • Slide Number 117
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                                                                                                                                          • Slide Number 119
                                                                                                                                          • Slide Number 120
                                                                                                                                          • Slide Number 121
                                                                                                                                          • Slide Number 122
                                                                                                                                          • Slide Number 123
                                                                                                                                          • Slide Number 124
                                                                                                                                          • Slide Number 125
                                                                                                                                          • DIC Take Home Messages
                                                                                                                                          • Slide Number 127
                                                                                                                                          • Slide Number 128

                                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                            ISTH Step by Step DIC Algorithm

                                                                                                                                            Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                                                                                                            US Based Validation of ISTH DIC Score

                                                                                                                                            When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                            Differential Diagnosis in DIC

                                                                                                                                            aHUS atypical hemolytic uremic syndrome

                                                                                                                                            HUS hemolytic uremic syndrome

                                                                                                                                            HIT heparin-induced thrombocytopenia

                                                                                                                                            ITP immune thrombocytopenic purpura

                                                                                                                                            TTP thrombotic thrombocytopenic purpura

                                                                                                                                            DIC and MAHA

                                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                            lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                                                                                                            When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                                                                                                            DIC Management Goals

                                                                                                                                            Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                                                            Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                                                                                                            DIC Management and Treatment

                                                                                                                                            Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                                                            Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                                                                                                            requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                                                                                                            Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                                                                                                            DIC Management Strategies

                                                                                                                                            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                                            Anticoagulant Factor Concentrate Treatment

                                                                                                                                            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                                            Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                                                                                            Anticoagulant Factor Concentrate Treatment Trials

                                                                                                                                            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                                            Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                                                                                            Markers of Thrombin amp Plasmin Generation in DIC

                                                                                                                                            D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                                                                                            Cut-off value

                                                                                                                                            Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                                                                                            degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                                                                                            D-dimer FDPs and DIC

                                                                                                                                            D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                                                                                            Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                                                                                            Follow Up of DIC State of Disease

                                                                                                                                            Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                                                                                            Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                                                                                            FMD-Dimer in DIC Major Differences

                                                                                                                                            onset of thrombosis

                                                                                                                                            days

                                                                                                                                            Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                                                                                            FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                                                                                            D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                                                                                            of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                                                                                            0

                                                                                                                                            20

                                                                                                                                            40

                                                                                                                                            60

                                                                                                                                            80

                                                                                                                                            100

                                                                                                                                            94 85 90N = 62

                                                                                                                                            Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                                                                                            Positivity of Test Results ISTH Score and Disease State

                                                                                                                                            Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                            Red bar positive for 2 points of DIC score

                                                                                                                                            Pink bar positive for 1-2 points of DIC score

                                                                                                                                            HT hematopoietic tumor

                                                                                                                                            IF infection

                                                                                                                                            SC solid cancer

                                                                                                                                            Markers in Patients with or without DIC

                                                                                                                                            Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                            HT hematopoietic tumorIF infectionSC solid cancer

                                                                                                                                            Comparing an Automated FM vs Manual FSP Test

                                                                                                                                            Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                                                                            Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                                                                            Automated (Mitsubishi) vs Automated (Stago)

                                                                                                                                            In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                                                                            Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                            In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                            In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                            In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                            Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                            No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                                                            Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                            Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                            Non Overt DIC Overt DIC

                                                                                                                                            AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                                                            Trends in Markers of DIC for Different Patients

                                                                                                                                            Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                                                            Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                                                            Trends in Markers of DIC for Different Patients

                                                                                                                                            Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                            FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                                                            28 day outcome survival

                                                                                                                                            28 day outcome death

                                                                                                                                            Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                            Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                            Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                                                            Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                            Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                            Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                                                            DIC Case Studies

                                                                                                                                            Case Study 1 - Presentation

                                                                                                                                            18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                            Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                                            WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                                            RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                                            Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                                            Hematocrit 195 401 ndash 510

                                                                                                                                            MCV 95 fL 790 ndash 922 fL

                                                                                                                                            MPV 12 fL 94 ndash 124 fL

                                                                                                                                            Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                                            Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                                            Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                                            PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                                            APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                                            Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                                            D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                            Case Study 1 ndash Microscopy

                                                                                                                                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                            Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                                            Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                                            DIC due to TF release by APL blasts

                                                                                                                                            Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                                            Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                            20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                                            Case Study 2 ndash Presentation

                                                                                                                                            TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                                            PT 30 sec 113 ndash 146 sec

                                                                                                                                            APTT 75 sec 25 ndash 34 sec

                                                                                                                                            D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                                            Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                                            pH 728 738 to 742

                                                                                                                                            PaO2 570 mmHg 80-100 mmHg

                                                                                                                                            WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                                            ALT 111 IUL 0ndash34 IUL

                                                                                                                                            AST 61 IUL 0ndash34 IUL

                                                                                                                                            BUN 303 mgdL 08-13 mgdL

                                                                                                                                            Case Study 2 ndash Lab Results

                                                                                                                                            Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                                            Case Study 2 ndash Diagnosis

                                                                                                                                            60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                                            Case Study 3 ndash Presentation

                                                                                                                                            TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                            PT 228 sec 113 ndash 146 sec

                                                                                                                                            APTT 45 sec 25 ndash 34 sec

                                                                                                                                            D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                            Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                            FV Normal 70-120

                                                                                                                                            FVII Normal 55-170

                                                                                                                                            FVIII Normal 60-150

                                                                                                                                            Protein C Normal 70-130

                                                                                                                                            Hb 134 gdL 14-16 gdL

                                                                                                                                            WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                            ALT 32 IUL 0ndash34 IUL

                                                                                                                                            AST 28 IUL 0ndash34 IUL

                                                                                                                                            BUN 09 mgdL 08-13 mgdL

                                                                                                                                            Case Study 3 ndash Lab Results

                                                                                                                                            Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                            Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                            Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                            Case Study 4 ndash Presentation

                                                                                                                                            TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                            PT 28 sec 113 ndash 146 sec

                                                                                                                                            APTT 71 sec 25 ndash 34 sec

                                                                                                                                            D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                            Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                            FV Normal 70-120

                                                                                                                                            FVII Normal 55-170

                                                                                                                                            FVIII Normal 60-150

                                                                                                                                            Protein C Normal 70-130

                                                                                                                                            Hb 158 gdL 14-16 gdL

                                                                                                                                            WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                            ALT 60 IUL 0ndash34 IUL

                                                                                                                                            AST 47 IUL 0ndash34 IUL

                                                                                                                                            BUN 38 mgdL 08-13 mgdL

                                                                                                                                            Case Study 4 ndash Lab Results

                                                                                                                                            Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                            Case Study 4 ndash Diagnosis

                                                                                                                                            55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                            Case Study 5 ndash Presentation

                                                                                                                                            Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                            Case Study 5 ndash Lab Results and Time Course

                                                                                                                                            Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                            TEST RESULT REFERENCE RANGE

                                                                                                                                            Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                            PT 215 sec 103 ndash 128 sec

                                                                                                                                            APTT 44 sec 26 ndash 36 sec

                                                                                                                                            D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                            Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                            FII FV FVIII Low Not reported (NR)

                                                                                                                                            FVII FIX FX vWF Normal NR

                                                                                                                                            Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                            DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                            dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                            (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                            (D) Illustration demonstrating repair

                                                                                                                                            Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                            Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                            29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                            Case Study 6 ndash Presentation

                                                                                                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                            Case Study 6 ndash Lab Results

                                                                                                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                            TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                            PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                            INR 658 1 ndash 125

                                                                                                                                            APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                            D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                            Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                            Albumin 28 gdL NR

                                                                                                                                            Hb 58 gdL NR

                                                                                                                                            LDH 1196 UL NR

                                                                                                                                            SGPT 144 IU NR

                                                                                                                                            SGOT 88 IU NR

                                                                                                                                            Bilirubin 32 mgdL NR

                                                                                                                                            DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                            day postop

                                                                                                                                            Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                            HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                            Case Study 6 ndash Discussion

                                                                                                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                            44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                            Case Study 7 ndash Presentation

                                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                            On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                            Case Study 7 ndash Presentation

                                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                            Case Study 7 ndash Lab Results vs Time

                                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                            Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                            Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                            On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                            Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                            DIC Take Home Messages

                                                                                                                                            Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                            Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                            DIC

                                                                                                                                            Thank you Questions

                                                                                                                                            • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                            • Learning Objectives
                                                                                                                                            • Slide Number 3
                                                                                                                                            • Slide Number 4
                                                                                                                                            • Slide Number 5
                                                                                                                                            • Slide Number 6
                                                                                                                                            • Slide Number 7
                                                                                                                                            • Slide Number 8
                                                                                                                                            • Wound Sealing
                                                                                                                                            • The Three Steps of Hemostasis
                                                                                                                                            • Vessel Wall
                                                                                                                                            • Slide Number 12
                                                                                                                                            • Slide Number 13
                                                                                                                                            • Platelet Structure UnactivatedActivated
                                                                                                                                            • Primary Hemostasis
                                                                                                                                            • Primary Hemostasis Assays
                                                                                                                                            • Slide Number 17
                                                                                                                                            • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                            • Slide Number 19
                                                                                                                                            • Coagulation factors
                                                                                                                                            • Coagulation Assay Mechanisms
                                                                                                                                            • Slide Number 22
                                                                                                                                            • Fibrin Formation
                                                                                                                                            • Slide Number 24
                                                                                                                                            • Fibrinolysis Overview
                                                                                                                                            • Fibrinolysis Overview
                                                                                                                                            • Slide Number 27
                                                                                                                                            • Fibrinolysis Releases D-dimers
                                                                                                                                            • Basic Pathophysiology of DIC
                                                                                                                                            • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                            • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                            • Clinical Conditions Associated With DIC
                                                                                                                                            • Frequency of DIC in Selected Disease States
                                                                                                                                            • Underlying Diseases in DIC Patients
                                                                                                                                            • Slide Number 36
                                                                                                                                            • Slide Number 37
                                                                                                                                            • Slide Number 38
                                                                                                                                            • Slide Number 39
                                                                                                                                            • Pathophysiology of DIC
                                                                                                                                            • Pathogenesis of DIC in Sepsis
                                                                                                                                            • Host Response in Severe Sepsis
                                                                                                                                            • Organ Failure in Severe Sepsis
                                                                                                                                            • Mechanism of DIC in Organ Failure
                                                                                                                                            • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                            • Slide Number 47
                                                                                                                                            • Diverse and Opposing Effects of Thrombin
                                                                                                                                            • Coagulation and Fibrinolysis in DIC
                                                                                                                                            • Mechanism of DIC
                                                                                                                                            • Pathophysiology of DIC
                                                                                                                                            • Pathophysiology of DIC - Mechanism
                                                                                                                                            • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                            • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                            • Pathophysiology of Overt DIC
                                                                                                                                            • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                            • Slide Number 57
                                                                                                                                            • Slide Number 58
                                                                                                                                            • Slide Number 59
                                                                                                                                            • Slide Number 60
                                                                                                                                            • Slide Number 61
                                                                                                                                            • BREAK
                                                                                                                                            • Diagnostic and Management Approach for DIC
                                                                                                                                            • Diagnosis of DIC
                                                                                                                                            • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                            • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                            • Slide Number 67
                                                                                                                                            • Slide Number 68
                                                                                                                                            • British Journal of Haematology Overt DIC Score
                                                                                                                                            • Slide Number 70
                                                                                                                                            • Slide Number 71
                                                                                                                                            • Slide Number 72
                                                                                                                                            • Slide Number 73
                                                                                                                                            • DIC Management Goals
                                                                                                                                            • DIC Management and Treatment
                                                                                                                                            • DIC Management Strategies
                                                                                                                                            • Anticoagulant Factor Concentrate Treatment
                                                                                                                                            • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                            • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                            • D-dimer FDPs and DIC
                                                                                                                                            • D-Dimer and FDPs in DIC
                                                                                                                                            • Follow Up of DIC State of Disease
                                                                                                                                            • FMD-Dimer in DIC Major Differences
                                                                                                                                            • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                            • Slide Number 85
                                                                                                                                            • Slide Number 86
                                                                                                                                            • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                            • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                            • Slide Number 94
                                                                                                                                            • Slide Number 95
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                                                                                                                                            • Slide Number 97
                                                                                                                                            • Slide Number 98
                                                                                                                                            • Slide Number 99
                                                                                                                                            • DIC Case Studies
                                                                                                                                            • Case Study 1 - Presentation
                                                                                                                                            • Case Study 1 ndash Lab Results
                                                                                                                                            • Case Study 1 ndash Microscopy
                                                                                                                                            • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                            • Slide Number 105
                                                                                                                                            • Slide Number 106
                                                                                                                                            • Slide Number 107
                                                                                                                                            • Slide Number 108
                                                                                                                                            • Slide Number 109
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                                                                                                                                            • Slide Number 122
                                                                                                                                            • Slide Number 123
                                                                                                                                            • Slide Number 124
                                                                                                                                            • Slide Number 125
                                                                                                                                            • DIC Take Home Messages
                                                                                                                                            • Slide Number 127
                                                                                                                                            • Slide Number 128

                                                                                                                                              Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6

                                                                                                                                              US Based Validation of ISTH DIC Score

                                                                                                                                              When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC

                                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                              Differential Diagnosis in DIC

                                                                                                                                              aHUS atypical hemolytic uremic syndrome

                                                                                                                                              HUS hemolytic uremic syndrome

                                                                                                                                              HIT heparin-induced thrombocytopenia

                                                                                                                                              ITP immune thrombocytopenic purpura

                                                                                                                                              TTP thrombotic thrombocytopenic purpura

                                                                                                                                              DIC and MAHA

                                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                              lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                                                                                                              When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                                                                                                              DIC Management Goals

                                                                                                                                              Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                                                              Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                                                                                                              DIC Management and Treatment

                                                                                                                                              Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                                                              Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                                                                                                              requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                                                                                                              Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                                                                                                              DIC Management Strategies

                                                                                                                                              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                                              Anticoagulant Factor Concentrate Treatment

                                                                                                                                              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                                              Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                                                                                              Anticoagulant Factor Concentrate Treatment Trials

                                                                                                                                              Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                                              Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                                                                                              Markers of Thrombin amp Plasmin Generation in DIC

                                                                                                                                              D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                                                                                              Cut-off value

                                                                                                                                              Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                                                                                              degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                                                                                              D-dimer FDPs and DIC

                                                                                                                                              D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                                                                                              Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                                                                                              Follow Up of DIC State of Disease

                                                                                                                                              Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                                                                                              Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                                                                                              FMD-Dimer in DIC Major Differences

                                                                                                                                              onset of thrombosis

                                                                                                                                              days

                                                                                                                                              Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                                                                                              FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                                                                                              D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                                                                                              of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                                                                                              0

                                                                                                                                              20

                                                                                                                                              40

                                                                                                                                              60

                                                                                                                                              80

                                                                                                                                              100

                                                                                                                                              94 85 90N = 62

                                                                                                                                              Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                                                                                              Positivity of Test Results ISTH Score and Disease State

                                                                                                                                              Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                              Red bar positive for 2 points of DIC score

                                                                                                                                              Pink bar positive for 1-2 points of DIC score

                                                                                                                                              HT hematopoietic tumor

                                                                                                                                              IF infection

                                                                                                                                              SC solid cancer

                                                                                                                                              Markers in Patients with or without DIC

                                                                                                                                              Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                              HT hematopoietic tumorIF infectionSC solid cancer

                                                                                                                                              Comparing an Automated FM vs Manual FSP Test

                                                                                                                                              Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                                                                              Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                                                                              Automated (Mitsubishi) vs Automated (Stago)

                                                                                                                                              In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                                                                              Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                              In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                              In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                              In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                              Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                              No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                                                              Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                              Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                              Non Overt DIC Overt DIC

                                                                                                                                              AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                                                              Trends in Markers of DIC for Different Patients

                                                                                                                                              Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                                                              Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                                                              Trends in Markers of DIC for Different Patients

                                                                                                                                              Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                              FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                                                              28 day outcome survival

                                                                                                                                              28 day outcome death

                                                                                                                                              Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                              Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                              Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                                                              Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                              Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                              Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                                                              DIC Case Studies

                                                                                                                                              Case Study 1 - Presentation

                                                                                                                                              18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                              Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                                              WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                                              RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                                              Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                                              Hematocrit 195 401 ndash 510

                                                                                                                                              MCV 95 fL 790 ndash 922 fL

                                                                                                                                              MPV 12 fL 94 ndash 124 fL

                                                                                                                                              Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                                              Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                                              Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                                              PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                                              APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                                              Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                                              D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                              Case Study 1 ndash Microscopy

                                                                                                                                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                              Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                                              Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                                              DIC due to TF release by APL blasts

                                                                                                                                              Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                                              Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                              20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                                              Case Study 2 ndash Presentation

                                                                                                                                              TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                                              PT 30 sec 113 ndash 146 sec

                                                                                                                                              APTT 75 sec 25 ndash 34 sec

                                                                                                                                              D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                                              Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                                              pH 728 738 to 742

                                                                                                                                              PaO2 570 mmHg 80-100 mmHg

                                                                                                                                              WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                                              ALT 111 IUL 0ndash34 IUL

                                                                                                                                              AST 61 IUL 0ndash34 IUL

                                                                                                                                              BUN 303 mgdL 08-13 mgdL

                                                                                                                                              Case Study 2 ndash Lab Results

                                                                                                                                              Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                                              Case Study 2 ndash Diagnosis

                                                                                                                                              60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                                              Case Study 3 ndash Presentation

                                                                                                                                              TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                              PT 228 sec 113 ndash 146 sec

                                                                                                                                              APTT 45 sec 25 ndash 34 sec

                                                                                                                                              D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                              Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                              FV Normal 70-120

                                                                                                                                              FVII Normal 55-170

                                                                                                                                              FVIII Normal 60-150

                                                                                                                                              Protein C Normal 70-130

                                                                                                                                              Hb 134 gdL 14-16 gdL

                                                                                                                                              WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                              ALT 32 IUL 0ndash34 IUL

                                                                                                                                              AST 28 IUL 0ndash34 IUL

                                                                                                                                              BUN 09 mgdL 08-13 mgdL

                                                                                                                                              Case Study 3 ndash Lab Results

                                                                                                                                              Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                              Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                              Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                              Case Study 4 ndash Presentation

                                                                                                                                              TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                              PT 28 sec 113 ndash 146 sec

                                                                                                                                              APTT 71 sec 25 ndash 34 sec

                                                                                                                                              D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                              Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                              FV Normal 70-120

                                                                                                                                              FVII Normal 55-170

                                                                                                                                              FVIII Normal 60-150

                                                                                                                                              Protein C Normal 70-130

                                                                                                                                              Hb 158 gdL 14-16 gdL

                                                                                                                                              WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                              ALT 60 IUL 0ndash34 IUL

                                                                                                                                              AST 47 IUL 0ndash34 IUL

                                                                                                                                              BUN 38 mgdL 08-13 mgdL

                                                                                                                                              Case Study 4 ndash Lab Results

                                                                                                                                              Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                              Case Study 4 ndash Diagnosis

                                                                                                                                              55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                              Case Study 5 ndash Presentation

                                                                                                                                              Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                              Case Study 5 ndash Lab Results and Time Course

                                                                                                                                              Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                              TEST RESULT REFERENCE RANGE

                                                                                                                                              Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                              PT 215 sec 103 ndash 128 sec

                                                                                                                                              APTT 44 sec 26 ndash 36 sec

                                                                                                                                              D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                              Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                              FII FV FVIII Low Not reported (NR)

                                                                                                                                              FVII FIX FX vWF Normal NR

                                                                                                                                              Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                              DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                              dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                              (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                              (D) Illustration demonstrating repair

                                                                                                                                              Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                              Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                              29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                              Case Study 6 ndash Presentation

                                                                                                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                              Case Study 6 ndash Lab Results

                                                                                                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                              TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                              PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                              INR 658 1 ndash 125

                                                                                                                                              APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                              D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                              Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                              Albumin 28 gdL NR

                                                                                                                                              Hb 58 gdL NR

                                                                                                                                              LDH 1196 UL NR

                                                                                                                                              SGPT 144 IU NR

                                                                                                                                              SGOT 88 IU NR

                                                                                                                                              Bilirubin 32 mgdL NR

                                                                                                                                              DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                              day postop

                                                                                                                                              Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                              HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                              Case Study 6 ndash Discussion

                                                                                                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                              44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                              Case Study 7 ndash Presentation

                                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                              On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                              Case Study 7 ndash Presentation

                                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                              Case Study 7 ndash Lab Results vs Time

                                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                              Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                              Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                              On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                              Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                              DIC Take Home Messages

                                                                                                                                              Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                              Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                              DIC

                                                                                                                                              Thank you Questions

                                                                                                                                              • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                              • Learning Objectives
                                                                                                                                              • Slide Number 3
                                                                                                                                              • Slide Number 4
                                                                                                                                              • Slide Number 5
                                                                                                                                              • Slide Number 6
                                                                                                                                              • Slide Number 7
                                                                                                                                              • Slide Number 8
                                                                                                                                              • Wound Sealing
                                                                                                                                              • The Three Steps of Hemostasis
                                                                                                                                              • Vessel Wall
                                                                                                                                              • Slide Number 12
                                                                                                                                              • Slide Number 13
                                                                                                                                              • Platelet Structure UnactivatedActivated
                                                                                                                                              • Primary Hemostasis
                                                                                                                                              • Primary Hemostasis Assays
                                                                                                                                              • Slide Number 17
                                                                                                                                              • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                              • Slide Number 19
                                                                                                                                              • Coagulation factors
                                                                                                                                              • Coagulation Assay Mechanisms
                                                                                                                                              • Slide Number 22
                                                                                                                                              • Fibrin Formation
                                                                                                                                              • Slide Number 24
                                                                                                                                              • Fibrinolysis Overview
                                                                                                                                              • Fibrinolysis Overview
                                                                                                                                              • Slide Number 27
                                                                                                                                              • Fibrinolysis Releases D-dimers
                                                                                                                                              • Basic Pathophysiology of DIC
                                                                                                                                              • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                              • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                              • Clinical Conditions Associated With DIC
                                                                                                                                              • Frequency of DIC in Selected Disease States
                                                                                                                                              • Underlying Diseases in DIC Patients
                                                                                                                                              • Slide Number 36
                                                                                                                                              • Slide Number 37
                                                                                                                                              • Slide Number 38
                                                                                                                                              • Slide Number 39
                                                                                                                                              • Pathophysiology of DIC
                                                                                                                                              • Pathogenesis of DIC in Sepsis
                                                                                                                                              • Host Response in Severe Sepsis
                                                                                                                                              • Organ Failure in Severe Sepsis
                                                                                                                                              • Mechanism of DIC in Organ Failure
                                                                                                                                              • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                              • Slide Number 47
                                                                                                                                              • Diverse and Opposing Effects of Thrombin
                                                                                                                                              • Coagulation and Fibrinolysis in DIC
                                                                                                                                              • Mechanism of DIC
                                                                                                                                              • Pathophysiology of DIC
                                                                                                                                              • Pathophysiology of DIC - Mechanism
                                                                                                                                              • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                              • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                              • Pathophysiology of Overt DIC
                                                                                                                                              • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                              • Slide Number 57
                                                                                                                                              • Slide Number 58
                                                                                                                                              • Slide Number 59
                                                                                                                                              • Slide Number 60
                                                                                                                                              • Slide Number 61
                                                                                                                                              • BREAK
                                                                                                                                              • Diagnostic and Management Approach for DIC
                                                                                                                                              • Diagnosis of DIC
                                                                                                                                              • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                              • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                              • Slide Number 67
                                                                                                                                              • Slide Number 68
                                                                                                                                              • British Journal of Haematology Overt DIC Score
                                                                                                                                              • Slide Number 70
                                                                                                                                              • Slide Number 71
                                                                                                                                              • Slide Number 72
                                                                                                                                              • Slide Number 73
                                                                                                                                              • DIC Management Goals
                                                                                                                                              • DIC Management and Treatment
                                                                                                                                              • DIC Management Strategies
                                                                                                                                              • Anticoagulant Factor Concentrate Treatment
                                                                                                                                              • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                              • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                              • D-dimer FDPs and DIC
                                                                                                                                              • D-Dimer and FDPs in DIC
                                                                                                                                              • Follow Up of DIC State of Disease
                                                                                                                                              • FMD-Dimer in DIC Major Differences
                                                                                                                                              • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                              • Slide Number 85
                                                                                                                                              • Slide Number 86
                                                                                                                                              • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                              • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                              • Slide Number 94
                                                                                                                                              • Slide Number 95
                                                                                                                                              • Slide Number 96
                                                                                                                                              • Slide Number 97
                                                                                                                                              • Slide Number 98
                                                                                                                                              • Slide Number 99
                                                                                                                                              • DIC Case Studies
                                                                                                                                              • Case Study 1 - Presentation
                                                                                                                                              • Case Study 1 ndash Lab Results
                                                                                                                                              • Case Study 1 ndash Microscopy
                                                                                                                                              • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                              • Slide Number 105
                                                                                                                                              • Slide Number 106
                                                                                                                                              • Slide Number 107
                                                                                                                                              • Slide Number 108
                                                                                                                                              • Slide Number 109
                                                                                                                                              • Slide Number 110
                                                                                                                                              • Slide Number 111
                                                                                                                                              • Slide Number 112
                                                                                                                                              • Slide Number 113
                                                                                                                                              • Slide Number 114
                                                                                                                                              • Slide Number 115
                                                                                                                                              • Slide Number 116
                                                                                                                                              • Slide Number 117
                                                                                                                                              • Slide Number 118
                                                                                                                                              • Slide Number 119
                                                                                                                                              • Slide Number 120
                                                                                                                                              • Slide Number 121
                                                                                                                                              • Slide Number 122
                                                                                                                                              • Slide Number 123
                                                                                                                                              • Slide Number 124
                                                                                                                                              • Slide Number 125
                                                                                                                                              • DIC Take Home Messages
                                                                                                                                              • Slide Number 127
                                                                                                                                              • Slide Number 128

                                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                Differential Diagnosis in DIC

                                                                                                                                                aHUS atypical hemolytic uremic syndrome

                                                                                                                                                HUS hemolytic uremic syndrome

                                                                                                                                                HIT heparin-induced thrombocytopenia

                                                                                                                                                ITP immune thrombocytopenic purpura

                                                                                                                                                TTP thrombotic thrombocytopenic purpura

                                                                                                                                                DIC and MAHA

                                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                                                                                                                When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                                                                                                                DIC Management Goals

                                                                                                                                                Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                                                                Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                                                                                                                DIC Management and Treatment

                                                                                                                                                Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                                                                Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                                                                                                                requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                                                                                                                Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                                                                                                                DIC Management Strategies

                                                                                                                                                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                                                Anticoagulant Factor Concentrate Treatment

                                                                                                                                                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                                                Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                                                                                                Anticoagulant Factor Concentrate Treatment Trials

                                                                                                                                                Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                                                Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                                                                                                Markers of Thrombin amp Plasmin Generation in DIC

                                                                                                                                                D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                                                                                                Cut-off value

                                                                                                                                                Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                                                                                                degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                                                                                                D-dimer FDPs and DIC

                                                                                                                                                D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                                                                                                Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                                                                                                Follow Up of DIC State of Disease

                                                                                                                                                Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                                                                                                Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                                                                                                FMD-Dimer in DIC Major Differences

                                                                                                                                                onset of thrombosis

                                                                                                                                                days

                                                                                                                                                Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                                                                                                FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                                                                                                D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                                                                                                of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                                                                                                0

                                                                                                                                                20

                                                                                                                                                40

                                                                                                                                                60

                                                                                                                                                80

                                                                                                                                                100

                                                                                                                                                94 85 90N = 62

                                                                                                                                                Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                                                                                                Positivity of Test Results ISTH Score and Disease State

                                                                                                                                                Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                                Red bar positive for 2 points of DIC score

                                                                                                                                                Pink bar positive for 1-2 points of DIC score

                                                                                                                                                HT hematopoietic tumor

                                                                                                                                                IF infection

                                                                                                                                                SC solid cancer

                                                                                                                                                Markers in Patients with or without DIC

                                                                                                                                                Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                                HT hematopoietic tumorIF infectionSC solid cancer

                                                                                                                                                Comparing an Automated FM vs Manual FSP Test

                                                                                                                                                Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                                                                                Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                                                                                Automated (Mitsubishi) vs Automated (Stago)

                                                                                                                                                In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                                                                                Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                                                                Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                Non Overt DIC Overt DIC

                                                                                                                                                AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                                                                Trends in Markers of DIC for Different Patients

                                                                                                                                                Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                                                                Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                                                                Trends in Markers of DIC for Different Patients

                                                                                                                                                Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                                                                28 day outcome survival

                                                                                                                                                28 day outcome death

                                                                                                                                                Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                                                                Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                                                                DIC Case Studies

                                                                                                                                                Case Study 1 - Presentation

                                                                                                                                                18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                                                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                                                WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                                                RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                                                Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                                                Hematocrit 195 401 ndash 510

                                                                                                                                                MCV 95 fL 790 ndash 922 fL

                                                                                                                                                MPV 12 fL 94 ndash 124 fL

                                                                                                                                                Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                                                Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                                                Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                                                PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                                                APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                                                Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                                                D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                                                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                Case Study 1 ndash Microscopy

                                                                                                                                                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                                                Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                                                DIC due to TF release by APL blasts

                                                                                                                                                Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                                                Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                                                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                                                Case Study 2 ndash Presentation

                                                                                                                                                TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                                                PT 30 sec 113 ndash 146 sec

                                                                                                                                                APTT 75 sec 25 ndash 34 sec

                                                                                                                                                D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                                                Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                                                pH 728 738 to 742

                                                                                                                                                PaO2 570 mmHg 80-100 mmHg

                                                                                                                                                WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                                                ALT 111 IUL 0ndash34 IUL

                                                                                                                                                AST 61 IUL 0ndash34 IUL

                                                                                                                                                BUN 303 mgdL 08-13 mgdL

                                                                                                                                                Case Study 2 ndash Lab Results

                                                                                                                                                Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                                                Case Study 2 ndash Diagnosis

                                                                                                                                                60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                                                Case Study 3 ndash Presentation

                                                                                                                                                TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                                PT 228 sec 113 ndash 146 sec

                                                                                                                                                APTT 45 sec 25 ndash 34 sec

                                                                                                                                                D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                                Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                                FV Normal 70-120

                                                                                                                                                FVII Normal 55-170

                                                                                                                                                FVIII Normal 60-150

                                                                                                                                                Protein C Normal 70-130

                                                                                                                                                Hb 134 gdL 14-16 gdL

                                                                                                                                                WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                                ALT 32 IUL 0ndash34 IUL

                                                                                                                                                AST 28 IUL 0ndash34 IUL

                                                                                                                                                BUN 09 mgdL 08-13 mgdL

                                                                                                                                                Case Study 3 ndash Lab Results

                                                                                                                                                Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                                Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                                Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                                Case Study 4 ndash Presentation

                                                                                                                                                TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                                PT 28 sec 113 ndash 146 sec

                                                                                                                                                APTT 71 sec 25 ndash 34 sec

                                                                                                                                                D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                                Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                                FV Normal 70-120

                                                                                                                                                FVII Normal 55-170

                                                                                                                                                FVIII Normal 60-150

                                                                                                                                                Protein C Normal 70-130

                                                                                                                                                Hb 158 gdL 14-16 gdL

                                                                                                                                                WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                                ALT 60 IUL 0ndash34 IUL

                                                                                                                                                AST 47 IUL 0ndash34 IUL

                                                                                                                                                BUN 38 mgdL 08-13 mgdL

                                                                                                                                                Case Study 4 ndash Lab Results

                                                                                                                                                Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                                Case Study 4 ndash Diagnosis

                                                                                                                                                55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                                Case Study 5 ndash Presentation

                                                                                                                                                Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                Case Study 5 ndash Lab Results and Time Course

                                                                                                                                                Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                TEST RESULT REFERENCE RANGE

                                                                                                                                                Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                                PT 215 sec 103 ndash 128 sec

                                                                                                                                                APTT 44 sec 26 ndash 36 sec

                                                                                                                                                D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                                Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                                FII FV FVIII Low Not reported (NR)

                                                                                                                                                FVII FIX FX vWF Normal NR

                                                                                                                                                Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                                DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                                dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                                (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                                (D) Illustration demonstrating repair

                                                                                                                                                Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                                Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                Case Study 6 ndash Presentation

                                                                                                                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                Case Study 6 ndash Lab Results

                                                                                                                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                INR 658 1 ndash 125

                                                                                                                                                APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                Albumin 28 gdL NR

                                                                                                                                                Hb 58 gdL NR

                                                                                                                                                LDH 1196 UL NR

                                                                                                                                                SGPT 144 IU NR

                                                                                                                                                SGOT 88 IU NR

                                                                                                                                                Bilirubin 32 mgdL NR

                                                                                                                                                DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                day postop

                                                                                                                                                Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                Case Study 6 ndash Discussion

                                                                                                                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                Case Study 7 ndash Presentation

                                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                Case Study 7 ndash Presentation

                                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                Case Study 7 ndash Lab Results vs Time

                                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                DIC Take Home Messages

                                                                                                                                                Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                DIC

                                                                                                                                                Thank you Questions

                                                                                                                                                • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                • Learning Objectives
                                                                                                                                                • Slide Number 3
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                                                                                                                                                • Slide Number 7
                                                                                                                                                • Slide Number 8
                                                                                                                                                • Wound Sealing
                                                                                                                                                • The Three Steps of Hemostasis
                                                                                                                                                • Vessel Wall
                                                                                                                                                • Slide Number 12
                                                                                                                                                • Slide Number 13
                                                                                                                                                • Platelet Structure UnactivatedActivated
                                                                                                                                                • Primary Hemostasis
                                                                                                                                                • Primary Hemostasis Assays
                                                                                                                                                • Slide Number 17
                                                                                                                                                • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                • Slide Number 19
                                                                                                                                                • Coagulation factors
                                                                                                                                                • Coagulation Assay Mechanisms
                                                                                                                                                • Slide Number 22
                                                                                                                                                • Fibrin Formation
                                                                                                                                                • Slide Number 24
                                                                                                                                                • Fibrinolysis Overview
                                                                                                                                                • Fibrinolysis Overview
                                                                                                                                                • Slide Number 27
                                                                                                                                                • Fibrinolysis Releases D-dimers
                                                                                                                                                • Basic Pathophysiology of DIC
                                                                                                                                                • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                • Clinical Conditions Associated With DIC
                                                                                                                                                • Frequency of DIC in Selected Disease States
                                                                                                                                                • Underlying Diseases in DIC Patients
                                                                                                                                                • Slide Number 36
                                                                                                                                                • Slide Number 37
                                                                                                                                                • Slide Number 38
                                                                                                                                                • Slide Number 39
                                                                                                                                                • Pathophysiology of DIC
                                                                                                                                                • Pathogenesis of DIC in Sepsis
                                                                                                                                                • Host Response in Severe Sepsis
                                                                                                                                                • Organ Failure in Severe Sepsis
                                                                                                                                                • Mechanism of DIC in Organ Failure
                                                                                                                                                • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                • Slide Number 47
                                                                                                                                                • Diverse and Opposing Effects of Thrombin
                                                                                                                                                • Coagulation and Fibrinolysis in DIC
                                                                                                                                                • Mechanism of DIC
                                                                                                                                                • Pathophysiology of DIC
                                                                                                                                                • Pathophysiology of DIC - Mechanism
                                                                                                                                                • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                • Pathophysiology of Overt DIC
                                                                                                                                                • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                • Slide Number 57
                                                                                                                                                • Slide Number 58
                                                                                                                                                • Slide Number 59
                                                                                                                                                • Slide Number 60
                                                                                                                                                • Slide Number 61
                                                                                                                                                • BREAK
                                                                                                                                                • Diagnostic and Management Approach for DIC
                                                                                                                                                • Diagnosis of DIC
                                                                                                                                                • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                • Slide Number 67
                                                                                                                                                • Slide Number 68
                                                                                                                                                • British Journal of Haematology Overt DIC Score
                                                                                                                                                • Slide Number 70
                                                                                                                                                • Slide Number 71
                                                                                                                                                • Slide Number 72
                                                                                                                                                • Slide Number 73
                                                                                                                                                • DIC Management Goals
                                                                                                                                                • DIC Management and Treatment
                                                                                                                                                • DIC Management Strategies
                                                                                                                                                • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                • D-dimer FDPs and DIC
                                                                                                                                                • D-Dimer and FDPs in DIC
                                                                                                                                                • Follow Up of DIC State of Disease
                                                                                                                                                • FMD-Dimer in DIC Major Differences
                                                                                                                                                • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                • Slide Number 85
                                                                                                                                                • Slide Number 86
                                                                                                                                                • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                • Slide Number 94
                                                                                                                                                • Slide Number 95
                                                                                                                                                • Slide Number 96
                                                                                                                                                • Slide Number 97
                                                                                                                                                • Slide Number 98
                                                                                                                                                • Slide Number 99
                                                                                                                                                • DIC Case Studies
                                                                                                                                                • Case Study 1 - Presentation
                                                                                                                                                • Case Study 1 ndash Lab Results
                                                                                                                                                • Case Study 1 ndash Microscopy
                                                                                                                                                • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                • Slide Number 105
                                                                                                                                                • Slide Number 106
                                                                                                                                                • Slide Number 107
                                                                                                                                                • Slide Number 108
                                                                                                                                                • Slide Number 109
                                                                                                                                                • Slide Number 110
                                                                                                                                                • Slide Number 111
                                                                                                                                                • Slide Number 112
                                                                                                                                                • Slide Number 113
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                                                                                                                                                • Slide Number 115
                                                                                                                                                • Slide Number 116
                                                                                                                                                • Slide Number 117
                                                                                                                                                • Slide Number 118
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                                                                                                                                                • Slide Number 121
                                                                                                                                                • Slide Number 122
                                                                                                                                                • Slide Number 123
                                                                                                                                                • Slide Number 124
                                                                                                                                                • Slide Number 125
                                                                                                                                                • DIC Take Home Messages
                                                                                                                                                • Slide Number 127
                                                                                                                                                • Slide Number 128

                                                                                                                                                  DIC and MAHA

                                                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                  lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)

                                                                                                                                                  When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation

                                                                                                                                                  DIC Management Goals

                                                                                                                                                  Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                                                                  Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                                                                                                                  DIC Management and Treatment

                                                                                                                                                  Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                                                                  Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                                                                                                                  requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                                                                                                                  Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                                                                                                                  DIC Management Strategies

                                                                                                                                                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                                                  Anticoagulant Factor Concentrate Treatment

                                                                                                                                                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                                                  Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                                                                                                  Anticoagulant Factor Concentrate Treatment Trials

                                                                                                                                                  Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                                                  Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                                                                                                  Markers of Thrombin amp Plasmin Generation in DIC

                                                                                                                                                  D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                                                                                                  Cut-off value

                                                                                                                                                  Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                                                                                                  degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                                                                                                  D-dimer FDPs and DIC

                                                                                                                                                  D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                                                                                                  Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                                                                                                  Follow Up of DIC State of Disease

                                                                                                                                                  Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                                                                                                  Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                                                                                                  FMD-Dimer in DIC Major Differences

                                                                                                                                                  onset of thrombosis

                                                                                                                                                  days

                                                                                                                                                  Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                                                                                                  FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                                                                                                  D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                                                                                                  of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                                                                                                  0

                                                                                                                                                  20

                                                                                                                                                  40

                                                                                                                                                  60

                                                                                                                                                  80

                                                                                                                                                  100

                                                                                                                                                  94 85 90N = 62

                                                                                                                                                  Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                                                                                                  Positivity of Test Results ISTH Score and Disease State

                                                                                                                                                  Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                                  Red bar positive for 2 points of DIC score

                                                                                                                                                  Pink bar positive for 1-2 points of DIC score

                                                                                                                                                  HT hematopoietic tumor

                                                                                                                                                  IF infection

                                                                                                                                                  SC solid cancer

                                                                                                                                                  Markers in Patients with or without DIC

                                                                                                                                                  Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                                  HT hematopoietic tumorIF infectionSC solid cancer

                                                                                                                                                  Comparing an Automated FM vs Manual FSP Test

                                                                                                                                                  Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                                                                                  Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                                                                                  Automated (Mitsubishi) vs Automated (Stago)

                                                                                                                                                  In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                                                                                  Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                  In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                  In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                  In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                  Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                  No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                                                                  Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                  Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                  Non Overt DIC Overt DIC

                                                                                                                                                  AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                                                                  Trends in Markers of DIC for Different Patients

                                                                                                                                                  Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                                                                  Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                                                                  Trends in Markers of DIC for Different Patients

                                                                                                                                                  Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                  FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                                                                  28 day outcome survival

                                                                                                                                                  28 day outcome death

                                                                                                                                                  Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                  Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                  Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                                                                  Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                  Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                  Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                                                                  DIC Case Studies

                                                                                                                                                  Case Study 1 - Presentation

                                                                                                                                                  18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                                                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                  Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                                                  WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                                                  RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                                                  Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                                                  Hematocrit 195 401 ndash 510

                                                                                                                                                  MCV 95 fL 790 ndash 922 fL

                                                                                                                                                  MPV 12 fL 94 ndash 124 fL

                                                                                                                                                  Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                                                  Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                                                  Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                                                  PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                                                  APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                                                  Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                                                  D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                                                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                  Case Study 1 ndash Microscopy

                                                                                                                                                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                  Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                                                  Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                                                  DIC due to TF release by APL blasts

                                                                                                                                                  Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                                                  Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                                                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                  20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                                                  Case Study 2 ndash Presentation

                                                                                                                                                  TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                                                  PT 30 sec 113 ndash 146 sec

                                                                                                                                                  APTT 75 sec 25 ndash 34 sec

                                                                                                                                                  D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                                                  Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                                                  pH 728 738 to 742

                                                                                                                                                  PaO2 570 mmHg 80-100 mmHg

                                                                                                                                                  WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                                                  ALT 111 IUL 0ndash34 IUL

                                                                                                                                                  AST 61 IUL 0ndash34 IUL

                                                                                                                                                  BUN 303 mgdL 08-13 mgdL

                                                                                                                                                  Case Study 2 ndash Lab Results

                                                                                                                                                  Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                                                  Case Study 2 ndash Diagnosis

                                                                                                                                                  60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                                                  Case Study 3 ndash Presentation

                                                                                                                                                  TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                                  PT 228 sec 113 ndash 146 sec

                                                                                                                                                  APTT 45 sec 25 ndash 34 sec

                                                                                                                                                  D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                                  Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                                  FV Normal 70-120

                                                                                                                                                  FVII Normal 55-170

                                                                                                                                                  FVIII Normal 60-150

                                                                                                                                                  Protein C Normal 70-130

                                                                                                                                                  Hb 134 gdL 14-16 gdL

                                                                                                                                                  WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                                  ALT 32 IUL 0ndash34 IUL

                                                                                                                                                  AST 28 IUL 0ndash34 IUL

                                                                                                                                                  BUN 09 mgdL 08-13 mgdL

                                                                                                                                                  Case Study 3 ndash Lab Results

                                                                                                                                                  Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                                  Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                                  Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                                  Case Study 4 ndash Presentation

                                                                                                                                                  TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                                  PT 28 sec 113 ndash 146 sec

                                                                                                                                                  APTT 71 sec 25 ndash 34 sec

                                                                                                                                                  D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                                  Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                                  FV Normal 70-120

                                                                                                                                                  FVII Normal 55-170

                                                                                                                                                  FVIII Normal 60-150

                                                                                                                                                  Protein C Normal 70-130

                                                                                                                                                  Hb 158 gdL 14-16 gdL

                                                                                                                                                  WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                                  ALT 60 IUL 0ndash34 IUL

                                                                                                                                                  AST 47 IUL 0ndash34 IUL

                                                                                                                                                  BUN 38 mgdL 08-13 mgdL

                                                                                                                                                  Case Study 4 ndash Lab Results

                                                                                                                                                  Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                                  Case Study 4 ndash Diagnosis

                                                                                                                                                  55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                                  Case Study 5 ndash Presentation

                                                                                                                                                  Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                  Case Study 5 ndash Lab Results and Time Course

                                                                                                                                                  Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                  TEST RESULT REFERENCE RANGE

                                                                                                                                                  Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                                  PT 215 sec 103 ndash 128 sec

                                                                                                                                                  APTT 44 sec 26 ndash 36 sec

                                                                                                                                                  D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                                  Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                                  FII FV FVIII Low Not reported (NR)

                                                                                                                                                  FVII FIX FX vWF Normal NR

                                                                                                                                                  Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                                  DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                                  dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                                  (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                                  (D) Illustration demonstrating repair

                                                                                                                                                  Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                                  Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                  29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                  Case Study 6 ndash Presentation

                                                                                                                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                  Case Study 6 ndash Lab Results

                                                                                                                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                  TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                  PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                  INR 658 1 ndash 125

                                                                                                                                                  APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                  D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                  Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                  Albumin 28 gdL NR

                                                                                                                                                  Hb 58 gdL NR

                                                                                                                                                  LDH 1196 UL NR

                                                                                                                                                  SGPT 144 IU NR

                                                                                                                                                  SGOT 88 IU NR

                                                                                                                                                  Bilirubin 32 mgdL NR

                                                                                                                                                  DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                  day postop

                                                                                                                                                  Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                  HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                  Case Study 6 ndash Discussion

                                                                                                                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                  44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                  Case Study 7 ndash Presentation

                                                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                  On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                  Case Study 7 ndash Presentation

                                                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                  Case Study 7 ndash Lab Results vs Time

                                                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                  Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                  Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                  On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                  Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                  DIC Take Home Messages

                                                                                                                                                  Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                  Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                  DIC

                                                                                                                                                  Thank you Questions

                                                                                                                                                  • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                  • Learning Objectives
                                                                                                                                                  • Slide Number 3
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                                                                                                                                                  • Slide Number 7
                                                                                                                                                  • Slide Number 8
                                                                                                                                                  • Wound Sealing
                                                                                                                                                  • The Three Steps of Hemostasis
                                                                                                                                                  • Vessel Wall
                                                                                                                                                  • Slide Number 12
                                                                                                                                                  • Slide Number 13
                                                                                                                                                  • Platelet Structure UnactivatedActivated
                                                                                                                                                  • Primary Hemostasis
                                                                                                                                                  • Primary Hemostasis Assays
                                                                                                                                                  • Slide Number 17
                                                                                                                                                  • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                  • Slide Number 19
                                                                                                                                                  • Coagulation factors
                                                                                                                                                  • Coagulation Assay Mechanisms
                                                                                                                                                  • Slide Number 22
                                                                                                                                                  • Fibrin Formation
                                                                                                                                                  • Slide Number 24
                                                                                                                                                  • Fibrinolysis Overview
                                                                                                                                                  • Fibrinolysis Overview
                                                                                                                                                  • Slide Number 27
                                                                                                                                                  • Fibrinolysis Releases D-dimers
                                                                                                                                                  • Basic Pathophysiology of DIC
                                                                                                                                                  • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                  • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                  • Clinical Conditions Associated With DIC
                                                                                                                                                  • Frequency of DIC in Selected Disease States
                                                                                                                                                  • Underlying Diseases in DIC Patients
                                                                                                                                                  • Slide Number 36
                                                                                                                                                  • Slide Number 37
                                                                                                                                                  • Slide Number 38
                                                                                                                                                  • Slide Number 39
                                                                                                                                                  • Pathophysiology of DIC
                                                                                                                                                  • Pathogenesis of DIC in Sepsis
                                                                                                                                                  • Host Response in Severe Sepsis
                                                                                                                                                  • Organ Failure in Severe Sepsis
                                                                                                                                                  • Mechanism of DIC in Organ Failure
                                                                                                                                                  • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                  • Slide Number 47
                                                                                                                                                  • Diverse and Opposing Effects of Thrombin
                                                                                                                                                  • Coagulation and Fibrinolysis in DIC
                                                                                                                                                  • Mechanism of DIC
                                                                                                                                                  • Pathophysiology of DIC
                                                                                                                                                  • Pathophysiology of DIC - Mechanism
                                                                                                                                                  • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                  • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                  • Pathophysiology of Overt DIC
                                                                                                                                                  • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                  • Slide Number 57
                                                                                                                                                  • Slide Number 58
                                                                                                                                                  • Slide Number 59
                                                                                                                                                  • Slide Number 60
                                                                                                                                                  • Slide Number 61
                                                                                                                                                  • BREAK
                                                                                                                                                  • Diagnostic and Management Approach for DIC
                                                                                                                                                  • Diagnosis of DIC
                                                                                                                                                  • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                  • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                  • Slide Number 67
                                                                                                                                                  • Slide Number 68
                                                                                                                                                  • British Journal of Haematology Overt DIC Score
                                                                                                                                                  • Slide Number 70
                                                                                                                                                  • Slide Number 71
                                                                                                                                                  • Slide Number 72
                                                                                                                                                  • Slide Number 73
                                                                                                                                                  • DIC Management Goals
                                                                                                                                                  • DIC Management and Treatment
                                                                                                                                                  • DIC Management Strategies
                                                                                                                                                  • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                  • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                  • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                  • D-dimer FDPs and DIC
                                                                                                                                                  • D-Dimer and FDPs in DIC
                                                                                                                                                  • Follow Up of DIC State of Disease
                                                                                                                                                  • FMD-Dimer in DIC Major Differences
                                                                                                                                                  • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                  • Slide Number 85
                                                                                                                                                  • Slide Number 86
                                                                                                                                                  • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                  • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                  • Slide Number 94
                                                                                                                                                  • Slide Number 95
                                                                                                                                                  • Slide Number 96
                                                                                                                                                  • Slide Number 97
                                                                                                                                                  • Slide Number 98
                                                                                                                                                  • Slide Number 99
                                                                                                                                                  • DIC Case Studies
                                                                                                                                                  • Case Study 1 - Presentation
                                                                                                                                                  • Case Study 1 ndash Lab Results
                                                                                                                                                  • Case Study 1 ndash Microscopy
                                                                                                                                                  • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                  • Slide Number 105
                                                                                                                                                  • Slide Number 106
                                                                                                                                                  • Slide Number 107
                                                                                                                                                  • Slide Number 108
                                                                                                                                                  • Slide Number 109
                                                                                                                                                  • Slide Number 110
                                                                                                                                                  • Slide Number 111
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                                                                                                                                                  • Slide Number 113
                                                                                                                                                  • Slide Number 114
                                                                                                                                                  • Slide Number 115
                                                                                                                                                  • Slide Number 116
                                                                                                                                                  • Slide Number 117
                                                                                                                                                  • Slide Number 118
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                                                                                                                                                  • Slide Number 120
                                                                                                                                                  • Slide Number 121
                                                                                                                                                  • Slide Number 122
                                                                                                                                                  • Slide Number 123
                                                                                                                                                  • Slide Number 124
                                                                                                                                                  • Slide Number 125
                                                                                                                                                  • DIC Take Home Messages
                                                                                                                                                  • Slide Number 127
                                                                                                                                                  • Slide Number 128

                                                                                                                                                    DIC Management Goals

                                                                                                                                                    Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                                                                    Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction

                                                                                                                                                    DIC Management and Treatment

                                                                                                                                                    Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                                                                    Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                                                                                                                    requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                                                                                                                    Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                                                                                                                    DIC Management Strategies

                                                                                                                                                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                                                    Anticoagulant Factor Concentrate Treatment

                                                                                                                                                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                                                    Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                                                                                                    Anticoagulant Factor Concentrate Treatment Trials

                                                                                                                                                    Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                                                    Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                                                                                                    Markers of Thrombin amp Plasmin Generation in DIC

                                                                                                                                                    D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                                                                                                    Cut-off value

                                                                                                                                                    Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                                                                                                    degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                                                                                                    D-dimer FDPs and DIC

                                                                                                                                                    D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                                                                                                    Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                                                                                                    Follow Up of DIC State of Disease

                                                                                                                                                    Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                                                                                                    Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                                                                                                    FMD-Dimer in DIC Major Differences

                                                                                                                                                    onset of thrombosis

                                                                                                                                                    days

                                                                                                                                                    Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                                                                                                    FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                                                                                                    D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                                                                                                    of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                                                                                                    0

                                                                                                                                                    20

                                                                                                                                                    40

                                                                                                                                                    60

                                                                                                                                                    80

                                                                                                                                                    100

                                                                                                                                                    94 85 90N = 62

                                                                                                                                                    Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                                                                                                    Positivity of Test Results ISTH Score and Disease State

                                                                                                                                                    Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                                    Red bar positive for 2 points of DIC score

                                                                                                                                                    Pink bar positive for 1-2 points of DIC score

                                                                                                                                                    HT hematopoietic tumor

                                                                                                                                                    IF infection

                                                                                                                                                    SC solid cancer

                                                                                                                                                    Markers in Patients with or without DIC

                                                                                                                                                    Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                                    HT hematopoietic tumorIF infectionSC solid cancer

                                                                                                                                                    Comparing an Automated FM vs Manual FSP Test

                                                                                                                                                    Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                                                                                    Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                                                                                    Automated (Mitsubishi) vs Automated (Stago)

                                                                                                                                                    In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                                                                                    Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                    In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                    In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                    In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                    Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                    No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                                                                    Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                    Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                    Non Overt DIC Overt DIC

                                                                                                                                                    AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                                                                    Trends in Markers of DIC for Different Patients

                                                                                                                                                    Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                                                                    Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                                                                    Trends in Markers of DIC for Different Patients

                                                                                                                                                    Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                    FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                                                                    28 day outcome survival

                                                                                                                                                    28 day outcome death

                                                                                                                                                    Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                    Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                    Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                                                                    Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                    Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                    Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                                                                    DIC Case Studies

                                                                                                                                                    Case Study 1 - Presentation

                                                                                                                                                    18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                                                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                    Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                                                    WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                                                    RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                                                    Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                                                    Hematocrit 195 401 ndash 510

                                                                                                                                                    MCV 95 fL 790 ndash 922 fL

                                                                                                                                                    MPV 12 fL 94 ndash 124 fL

                                                                                                                                                    Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                                                    Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                                                    Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                                                    PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                                                    APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                                                    Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                                                    D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                                                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                    Case Study 1 ndash Microscopy

                                                                                                                                                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                    Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                                                    Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                                                    DIC due to TF release by APL blasts

                                                                                                                                                    Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                                                    Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                                                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                    20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                                                    Case Study 2 ndash Presentation

                                                                                                                                                    TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                                                    PT 30 sec 113 ndash 146 sec

                                                                                                                                                    APTT 75 sec 25 ndash 34 sec

                                                                                                                                                    D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                                                    Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                                                    pH 728 738 to 742

                                                                                                                                                    PaO2 570 mmHg 80-100 mmHg

                                                                                                                                                    WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                                                    ALT 111 IUL 0ndash34 IUL

                                                                                                                                                    AST 61 IUL 0ndash34 IUL

                                                                                                                                                    BUN 303 mgdL 08-13 mgdL

                                                                                                                                                    Case Study 2 ndash Lab Results

                                                                                                                                                    Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                                                    Case Study 2 ndash Diagnosis

                                                                                                                                                    60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                                                    Case Study 3 ndash Presentation

                                                                                                                                                    TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                                    PT 228 sec 113 ndash 146 sec

                                                                                                                                                    APTT 45 sec 25 ndash 34 sec

                                                                                                                                                    D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                                    Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                                    FV Normal 70-120

                                                                                                                                                    FVII Normal 55-170

                                                                                                                                                    FVIII Normal 60-150

                                                                                                                                                    Protein C Normal 70-130

                                                                                                                                                    Hb 134 gdL 14-16 gdL

                                                                                                                                                    WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                                    ALT 32 IUL 0ndash34 IUL

                                                                                                                                                    AST 28 IUL 0ndash34 IUL

                                                                                                                                                    BUN 09 mgdL 08-13 mgdL

                                                                                                                                                    Case Study 3 ndash Lab Results

                                                                                                                                                    Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                                    Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                                    Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                                    Case Study 4 ndash Presentation

                                                                                                                                                    TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                                    PT 28 sec 113 ndash 146 sec

                                                                                                                                                    APTT 71 sec 25 ndash 34 sec

                                                                                                                                                    D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                                    Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                                    FV Normal 70-120

                                                                                                                                                    FVII Normal 55-170

                                                                                                                                                    FVIII Normal 60-150

                                                                                                                                                    Protein C Normal 70-130

                                                                                                                                                    Hb 158 gdL 14-16 gdL

                                                                                                                                                    WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                                    ALT 60 IUL 0ndash34 IUL

                                                                                                                                                    AST 47 IUL 0ndash34 IUL

                                                                                                                                                    BUN 38 mgdL 08-13 mgdL

                                                                                                                                                    Case Study 4 ndash Lab Results

                                                                                                                                                    Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                                    Case Study 4 ndash Diagnosis

                                                                                                                                                    55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                                    Case Study 5 ndash Presentation

                                                                                                                                                    Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                    Case Study 5 ndash Lab Results and Time Course

                                                                                                                                                    Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                    TEST RESULT REFERENCE RANGE

                                                                                                                                                    Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                                    PT 215 sec 103 ndash 128 sec

                                                                                                                                                    APTT 44 sec 26 ndash 36 sec

                                                                                                                                                    D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                                    Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                                    FII FV FVIII Low Not reported (NR)

                                                                                                                                                    FVII FIX FX vWF Normal NR

                                                                                                                                                    Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                                    DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                                    dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                                    (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                                    (D) Illustration demonstrating repair

                                                                                                                                                    Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                                    Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                    29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                    Case Study 6 ndash Presentation

                                                                                                                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                    Case Study 6 ndash Lab Results

                                                                                                                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                    TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                    PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                    INR 658 1 ndash 125

                                                                                                                                                    APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                    D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                    Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                    Albumin 28 gdL NR

                                                                                                                                                    Hb 58 gdL NR

                                                                                                                                                    LDH 1196 UL NR

                                                                                                                                                    SGPT 144 IU NR

                                                                                                                                                    SGOT 88 IU NR

                                                                                                                                                    Bilirubin 32 mgdL NR

                                                                                                                                                    DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                    day postop

                                                                                                                                                    Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                    HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                    Case Study 6 ndash Discussion

                                                                                                                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                    44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                    Case Study 7 ndash Presentation

                                                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                    On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                    Case Study 7 ndash Presentation

                                                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                    Case Study 7 ndash Lab Results vs Time

                                                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                    Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                    Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                    On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                    Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                    DIC Take Home Messages

                                                                                                                                                    Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                    Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                    DIC

                                                                                                                                                    Thank you Questions

                                                                                                                                                    • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                    • Learning Objectives
                                                                                                                                                    • Slide Number 3
                                                                                                                                                    • Slide Number 4
                                                                                                                                                    • Slide Number 5
                                                                                                                                                    • Slide Number 6
                                                                                                                                                    • Slide Number 7
                                                                                                                                                    • Slide Number 8
                                                                                                                                                    • Wound Sealing
                                                                                                                                                    • The Three Steps of Hemostasis
                                                                                                                                                    • Vessel Wall
                                                                                                                                                    • Slide Number 12
                                                                                                                                                    • Slide Number 13
                                                                                                                                                    • Platelet Structure UnactivatedActivated
                                                                                                                                                    • Primary Hemostasis
                                                                                                                                                    • Primary Hemostasis Assays
                                                                                                                                                    • Slide Number 17
                                                                                                                                                    • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                    • Slide Number 19
                                                                                                                                                    • Coagulation factors
                                                                                                                                                    • Coagulation Assay Mechanisms
                                                                                                                                                    • Slide Number 22
                                                                                                                                                    • Fibrin Formation
                                                                                                                                                    • Slide Number 24
                                                                                                                                                    • Fibrinolysis Overview
                                                                                                                                                    • Fibrinolysis Overview
                                                                                                                                                    • Slide Number 27
                                                                                                                                                    • Fibrinolysis Releases D-dimers
                                                                                                                                                    • Basic Pathophysiology of DIC
                                                                                                                                                    • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                    • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                    • Clinical Conditions Associated With DIC
                                                                                                                                                    • Frequency of DIC in Selected Disease States
                                                                                                                                                    • Underlying Diseases in DIC Patients
                                                                                                                                                    • Slide Number 36
                                                                                                                                                    • Slide Number 37
                                                                                                                                                    • Slide Number 38
                                                                                                                                                    • Slide Number 39
                                                                                                                                                    • Pathophysiology of DIC
                                                                                                                                                    • Pathogenesis of DIC in Sepsis
                                                                                                                                                    • Host Response in Severe Sepsis
                                                                                                                                                    • Organ Failure in Severe Sepsis
                                                                                                                                                    • Mechanism of DIC in Organ Failure
                                                                                                                                                    • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                    • Slide Number 47
                                                                                                                                                    • Diverse and Opposing Effects of Thrombin
                                                                                                                                                    • Coagulation and Fibrinolysis in DIC
                                                                                                                                                    • Mechanism of DIC
                                                                                                                                                    • Pathophysiology of DIC
                                                                                                                                                    • Pathophysiology of DIC - Mechanism
                                                                                                                                                    • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                    • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                    • Pathophysiology of Overt DIC
                                                                                                                                                    • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                    • Slide Number 57
                                                                                                                                                    • Slide Number 58
                                                                                                                                                    • Slide Number 59
                                                                                                                                                    • Slide Number 60
                                                                                                                                                    • Slide Number 61
                                                                                                                                                    • BREAK
                                                                                                                                                    • Diagnostic and Management Approach for DIC
                                                                                                                                                    • Diagnosis of DIC
                                                                                                                                                    • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                    • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                    • Slide Number 67
                                                                                                                                                    • Slide Number 68
                                                                                                                                                    • British Journal of Haematology Overt DIC Score
                                                                                                                                                    • Slide Number 70
                                                                                                                                                    • Slide Number 71
                                                                                                                                                    • Slide Number 72
                                                                                                                                                    • Slide Number 73
                                                                                                                                                    • DIC Management Goals
                                                                                                                                                    • DIC Management and Treatment
                                                                                                                                                    • DIC Management Strategies
                                                                                                                                                    • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                    • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                    • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                    • D-dimer FDPs and DIC
                                                                                                                                                    • D-Dimer and FDPs in DIC
                                                                                                                                                    • Follow Up of DIC State of Disease
                                                                                                                                                    • FMD-Dimer in DIC Major Differences
                                                                                                                                                    • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                    • Slide Number 85
                                                                                                                                                    • Slide Number 86
                                                                                                                                                    • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                    • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                    • Slide Number 94
                                                                                                                                                    • Slide Number 95
                                                                                                                                                    • Slide Number 96
                                                                                                                                                    • Slide Number 97
                                                                                                                                                    • Slide Number 98
                                                                                                                                                    • Slide Number 99
                                                                                                                                                    • DIC Case Studies
                                                                                                                                                    • Case Study 1 - Presentation
                                                                                                                                                    • Case Study 1 ndash Lab Results
                                                                                                                                                    • Case Study 1 ndash Microscopy
                                                                                                                                                    • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                    • Slide Number 105
                                                                                                                                                    • Slide Number 106
                                                                                                                                                    • Slide Number 107
                                                                                                                                                    • Slide Number 108
                                                                                                                                                    • Slide Number 109
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                                                                                                                                                    • Slide Number 123
                                                                                                                                                    • Slide Number 124
                                                                                                                                                    • Slide Number 125
                                                                                                                                                    • DIC Take Home Messages
                                                                                                                                                    • Slide Number 127
                                                                                                                                                    • Slide Number 128

                                                                                                                                                      DIC Management and Treatment

                                                                                                                                                      Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7

                                                                                                                                                      Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)

                                                                                                                                                      requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)

                                                                                                                                                      Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia

                                                                                                                                                      DIC Management Strategies

                                                                                                                                                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                                                      Anticoagulant Factor Concentrate Treatment

                                                                                                                                                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                                                      Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                                                                                                      Anticoagulant Factor Concentrate Treatment Trials

                                                                                                                                                      Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                                                      Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                                                                                                      Markers of Thrombin amp Plasmin Generation in DIC

                                                                                                                                                      D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                                                                                                      Cut-off value

                                                                                                                                                      Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                                                                                                      degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                                                                                                      D-dimer FDPs and DIC

                                                                                                                                                      D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                                                                                                      Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                                                                                                      Follow Up of DIC State of Disease

                                                                                                                                                      Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                                                                                                      Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                                                                                                      FMD-Dimer in DIC Major Differences

                                                                                                                                                      onset of thrombosis

                                                                                                                                                      days

                                                                                                                                                      Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                                                                                                      FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                                                                                                      D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                                                                                                      of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                                                                                                      0

                                                                                                                                                      20

                                                                                                                                                      40

                                                                                                                                                      60

                                                                                                                                                      80

                                                                                                                                                      100

                                                                                                                                                      94 85 90N = 62

                                                                                                                                                      Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                                                                                                      Positivity of Test Results ISTH Score and Disease State

                                                                                                                                                      Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                                      Red bar positive for 2 points of DIC score

                                                                                                                                                      Pink bar positive for 1-2 points of DIC score

                                                                                                                                                      HT hematopoietic tumor

                                                                                                                                                      IF infection

                                                                                                                                                      SC solid cancer

                                                                                                                                                      Markers in Patients with or without DIC

                                                                                                                                                      Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                                      HT hematopoietic tumorIF infectionSC solid cancer

                                                                                                                                                      Comparing an Automated FM vs Manual FSP Test

                                                                                                                                                      Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                                                                                      Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                                                                                      Automated (Mitsubishi) vs Automated (Stago)

                                                                                                                                                      In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                                                                                      Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                      In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                      In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                      In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                      Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                      No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                                                                      Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                      Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                      Non Overt DIC Overt DIC

                                                                                                                                                      AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                                                                      Trends in Markers of DIC for Different Patients

                                                                                                                                                      Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                                                                      Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                                                                      Trends in Markers of DIC for Different Patients

                                                                                                                                                      Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                      FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                                                                      28 day outcome survival

                                                                                                                                                      28 day outcome death

                                                                                                                                                      Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                      Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                      Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                                                                      Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                      Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                      Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                                                                      DIC Case Studies

                                                                                                                                                      Case Study 1 - Presentation

                                                                                                                                                      18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                                                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                      Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                                                      WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                                                      RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                                                      Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                                                      Hematocrit 195 401 ndash 510

                                                                                                                                                      MCV 95 fL 790 ndash 922 fL

                                                                                                                                                      MPV 12 fL 94 ndash 124 fL

                                                                                                                                                      Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                                                      Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                                                      Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                                                      PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                                                      APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                                                      Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                                                      D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                                                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                      Case Study 1 ndash Microscopy

                                                                                                                                                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                      Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                                                      Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                                                      DIC due to TF release by APL blasts

                                                                                                                                                      Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                                                      Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                                                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                      20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                                                      Case Study 2 ndash Presentation

                                                                                                                                                      TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                                                      PT 30 sec 113 ndash 146 sec

                                                                                                                                                      APTT 75 sec 25 ndash 34 sec

                                                                                                                                                      D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                                                      Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                                                      pH 728 738 to 742

                                                                                                                                                      PaO2 570 mmHg 80-100 mmHg

                                                                                                                                                      WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                                                      ALT 111 IUL 0ndash34 IUL

                                                                                                                                                      AST 61 IUL 0ndash34 IUL

                                                                                                                                                      BUN 303 mgdL 08-13 mgdL

                                                                                                                                                      Case Study 2 ndash Lab Results

                                                                                                                                                      Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                                                      Case Study 2 ndash Diagnosis

                                                                                                                                                      60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                                                      Case Study 3 ndash Presentation

                                                                                                                                                      TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                                      PT 228 sec 113 ndash 146 sec

                                                                                                                                                      APTT 45 sec 25 ndash 34 sec

                                                                                                                                                      D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                                      Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                                      FV Normal 70-120

                                                                                                                                                      FVII Normal 55-170

                                                                                                                                                      FVIII Normal 60-150

                                                                                                                                                      Protein C Normal 70-130

                                                                                                                                                      Hb 134 gdL 14-16 gdL

                                                                                                                                                      WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                                      ALT 32 IUL 0ndash34 IUL

                                                                                                                                                      AST 28 IUL 0ndash34 IUL

                                                                                                                                                      BUN 09 mgdL 08-13 mgdL

                                                                                                                                                      Case Study 3 ndash Lab Results

                                                                                                                                                      Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                                      Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                                      Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                                      Case Study 4 ndash Presentation

                                                                                                                                                      TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                                      PT 28 sec 113 ndash 146 sec

                                                                                                                                                      APTT 71 sec 25 ndash 34 sec

                                                                                                                                                      D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                                      Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                                      FV Normal 70-120

                                                                                                                                                      FVII Normal 55-170

                                                                                                                                                      FVIII Normal 60-150

                                                                                                                                                      Protein C Normal 70-130

                                                                                                                                                      Hb 158 gdL 14-16 gdL

                                                                                                                                                      WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                                      ALT 60 IUL 0ndash34 IUL

                                                                                                                                                      AST 47 IUL 0ndash34 IUL

                                                                                                                                                      BUN 38 mgdL 08-13 mgdL

                                                                                                                                                      Case Study 4 ndash Lab Results

                                                                                                                                                      Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                                      Case Study 4 ndash Diagnosis

                                                                                                                                                      55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                                      Case Study 5 ndash Presentation

                                                                                                                                                      Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                      Case Study 5 ndash Lab Results and Time Course

                                                                                                                                                      Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                      TEST RESULT REFERENCE RANGE

                                                                                                                                                      Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                                      PT 215 sec 103 ndash 128 sec

                                                                                                                                                      APTT 44 sec 26 ndash 36 sec

                                                                                                                                                      D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                                      Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                                      FII FV FVIII Low Not reported (NR)

                                                                                                                                                      FVII FIX FX vWF Normal NR

                                                                                                                                                      Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                                      DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                                      dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                                      (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                                      (D) Illustration demonstrating repair

                                                                                                                                                      Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                                      Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                      29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                      Case Study 6 ndash Presentation

                                                                                                                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                      Case Study 6 ndash Lab Results

                                                                                                                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                      TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                      PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                      INR 658 1 ndash 125

                                                                                                                                                      APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                      D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                      Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                      Albumin 28 gdL NR

                                                                                                                                                      Hb 58 gdL NR

                                                                                                                                                      LDH 1196 UL NR

                                                                                                                                                      SGPT 144 IU NR

                                                                                                                                                      SGOT 88 IU NR

                                                                                                                                                      Bilirubin 32 mgdL NR

                                                                                                                                                      DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                      day postop

                                                                                                                                                      Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                      HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                      Case Study 6 ndash Discussion

                                                                                                                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                      44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                      Case Study 7 ndash Presentation

                                                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                      On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                      Case Study 7 ndash Presentation

                                                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                      Case Study 7 ndash Lab Results vs Time

                                                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                      Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                      Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                      On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                      Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                      DIC Take Home Messages

                                                                                                                                                      Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                      Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                      DIC

                                                                                                                                                      Thank you Questions

                                                                                                                                                      • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                      • Learning Objectives
                                                                                                                                                      • Slide Number 3
                                                                                                                                                      • Slide Number 4
                                                                                                                                                      • Slide Number 5
                                                                                                                                                      • Slide Number 6
                                                                                                                                                      • Slide Number 7
                                                                                                                                                      • Slide Number 8
                                                                                                                                                      • Wound Sealing
                                                                                                                                                      • The Three Steps of Hemostasis
                                                                                                                                                      • Vessel Wall
                                                                                                                                                      • Slide Number 12
                                                                                                                                                      • Slide Number 13
                                                                                                                                                      • Platelet Structure UnactivatedActivated
                                                                                                                                                      • Primary Hemostasis
                                                                                                                                                      • Primary Hemostasis Assays
                                                                                                                                                      • Slide Number 17
                                                                                                                                                      • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                      • Slide Number 19
                                                                                                                                                      • Coagulation factors
                                                                                                                                                      • Coagulation Assay Mechanisms
                                                                                                                                                      • Slide Number 22
                                                                                                                                                      • Fibrin Formation
                                                                                                                                                      • Slide Number 24
                                                                                                                                                      • Fibrinolysis Overview
                                                                                                                                                      • Fibrinolysis Overview
                                                                                                                                                      • Slide Number 27
                                                                                                                                                      • Fibrinolysis Releases D-dimers
                                                                                                                                                      • Basic Pathophysiology of DIC
                                                                                                                                                      • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                      • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                      • Clinical Conditions Associated With DIC
                                                                                                                                                      • Frequency of DIC in Selected Disease States
                                                                                                                                                      • Underlying Diseases in DIC Patients
                                                                                                                                                      • Slide Number 36
                                                                                                                                                      • Slide Number 37
                                                                                                                                                      • Slide Number 38
                                                                                                                                                      • Slide Number 39
                                                                                                                                                      • Pathophysiology of DIC
                                                                                                                                                      • Pathogenesis of DIC in Sepsis
                                                                                                                                                      • Host Response in Severe Sepsis
                                                                                                                                                      • Organ Failure in Severe Sepsis
                                                                                                                                                      • Mechanism of DIC in Organ Failure
                                                                                                                                                      • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                      • Slide Number 47
                                                                                                                                                      • Diverse and Opposing Effects of Thrombin
                                                                                                                                                      • Coagulation and Fibrinolysis in DIC
                                                                                                                                                      • Mechanism of DIC
                                                                                                                                                      • Pathophysiology of DIC
                                                                                                                                                      • Pathophysiology of DIC - Mechanism
                                                                                                                                                      • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                      • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                      • Pathophysiology of Overt DIC
                                                                                                                                                      • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                      • Slide Number 57
                                                                                                                                                      • Slide Number 58
                                                                                                                                                      • Slide Number 59
                                                                                                                                                      • Slide Number 60
                                                                                                                                                      • Slide Number 61
                                                                                                                                                      • BREAK
                                                                                                                                                      • Diagnostic and Management Approach for DIC
                                                                                                                                                      • Diagnosis of DIC
                                                                                                                                                      • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                      • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                      • Slide Number 67
                                                                                                                                                      • Slide Number 68
                                                                                                                                                      • British Journal of Haematology Overt DIC Score
                                                                                                                                                      • Slide Number 70
                                                                                                                                                      • Slide Number 71
                                                                                                                                                      • Slide Number 72
                                                                                                                                                      • Slide Number 73
                                                                                                                                                      • DIC Management Goals
                                                                                                                                                      • DIC Management and Treatment
                                                                                                                                                      • DIC Management Strategies
                                                                                                                                                      • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                      • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                      • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                      • D-dimer FDPs and DIC
                                                                                                                                                      • D-Dimer and FDPs in DIC
                                                                                                                                                      • Follow Up of DIC State of Disease
                                                                                                                                                      • FMD-Dimer in DIC Major Differences
                                                                                                                                                      • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                      • Slide Number 85
                                                                                                                                                      • Slide Number 86
                                                                                                                                                      • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                      • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                      • Slide Number 94
                                                                                                                                                      • Slide Number 95
                                                                                                                                                      • Slide Number 96
                                                                                                                                                      • Slide Number 97
                                                                                                                                                      • Slide Number 98
                                                                                                                                                      • Slide Number 99
                                                                                                                                                      • DIC Case Studies
                                                                                                                                                      • Case Study 1 - Presentation
                                                                                                                                                      • Case Study 1 ndash Lab Results
                                                                                                                                                      • Case Study 1 ndash Microscopy
                                                                                                                                                      • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                      • Slide Number 105
                                                                                                                                                      • Slide Number 106
                                                                                                                                                      • Slide Number 107
                                                                                                                                                      • Slide Number 108
                                                                                                                                                      • Slide Number 109
                                                                                                                                                      • Slide Number 110
                                                                                                                                                      • Slide Number 111
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                                                                                                                                                      • Slide Number 113
                                                                                                                                                      • Slide Number 114
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                                                                                                                                                      • Slide Number 117
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                                                                                                                                                      • Slide Number 120
                                                                                                                                                      • Slide Number 121
                                                                                                                                                      • Slide Number 122
                                                                                                                                                      • Slide Number 123
                                                                                                                                                      • Slide Number 124
                                                                                                                                                      • Slide Number 125
                                                                                                                                                      • DIC Take Home Messages
                                                                                                                                                      • Slide Number 127
                                                                                                                                                      • Slide Number 128

                                                                                                                                                        DIC Management Strategies

                                                                                                                                                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                                                        Anticoagulant Factor Concentrate Treatment

                                                                                                                                                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                                                        Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                                                                                                        Anticoagulant Factor Concentrate Treatment Trials

                                                                                                                                                        Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                                                        Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                                                                                                        Markers of Thrombin amp Plasmin Generation in DIC

                                                                                                                                                        D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                                                                                                        Cut-off value

                                                                                                                                                        Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                                                                                                        degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                                                                                                        D-dimer FDPs and DIC

                                                                                                                                                        D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                                                                                                        Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                                                                                                        Follow Up of DIC State of Disease

                                                                                                                                                        Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                                                                                                        Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                                                                                                        FMD-Dimer in DIC Major Differences

                                                                                                                                                        onset of thrombosis

                                                                                                                                                        days

                                                                                                                                                        Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                                                                                                        FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                                                                                                        D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                                                                                                        of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                                                                                                        0

                                                                                                                                                        20

                                                                                                                                                        40

                                                                                                                                                        60

                                                                                                                                                        80

                                                                                                                                                        100

                                                                                                                                                        94 85 90N = 62

                                                                                                                                                        Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                                                                                                        Positivity of Test Results ISTH Score and Disease State

                                                                                                                                                        Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                                        Red bar positive for 2 points of DIC score

                                                                                                                                                        Pink bar positive for 1-2 points of DIC score

                                                                                                                                                        HT hematopoietic tumor

                                                                                                                                                        IF infection

                                                                                                                                                        SC solid cancer

                                                                                                                                                        Markers in Patients with or without DIC

                                                                                                                                                        Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                                        HT hematopoietic tumorIF infectionSC solid cancer

                                                                                                                                                        Comparing an Automated FM vs Manual FSP Test

                                                                                                                                                        Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                                                                                        Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                                                                                        Automated (Mitsubishi) vs Automated (Stago)

                                                                                                                                                        In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                                                                                        Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                        In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                        In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                        In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                        Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                        No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                                                                        Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                        Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                        Non Overt DIC Overt DIC

                                                                                                                                                        AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                                                                        Trends in Markers of DIC for Different Patients

                                                                                                                                                        Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                                                                        Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                                                                        Trends in Markers of DIC for Different Patients

                                                                                                                                                        Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                        FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                                                                        28 day outcome survival

                                                                                                                                                        28 day outcome death

                                                                                                                                                        Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                        Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                        Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                                                                        Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                        Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                        Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                                                                        DIC Case Studies

                                                                                                                                                        Case Study 1 - Presentation

                                                                                                                                                        18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                                                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                        Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                                                        WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                                                        RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                                                        Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                                                        Hematocrit 195 401 ndash 510

                                                                                                                                                        MCV 95 fL 790 ndash 922 fL

                                                                                                                                                        MPV 12 fL 94 ndash 124 fL

                                                                                                                                                        Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                                                        Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                                                        Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                                                        PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                                                        APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                                                        Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                                                        D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                                                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                        Case Study 1 ndash Microscopy

                                                                                                                                                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                        Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                                                        Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                                                        DIC due to TF release by APL blasts

                                                                                                                                                        Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                                                        Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                                                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                        20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                                                        Case Study 2 ndash Presentation

                                                                                                                                                        TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                                                        PT 30 sec 113 ndash 146 sec

                                                                                                                                                        APTT 75 sec 25 ndash 34 sec

                                                                                                                                                        D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                                                        Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                                                        pH 728 738 to 742

                                                                                                                                                        PaO2 570 mmHg 80-100 mmHg

                                                                                                                                                        WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                                                        ALT 111 IUL 0ndash34 IUL

                                                                                                                                                        AST 61 IUL 0ndash34 IUL

                                                                                                                                                        BUN 303 mgdL 08-13 mgdL

                                                                                                                                                        Case Study 2 ndash Lab Results

                                                                                                                                                        Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                                                        Case Study 2 ndash Diagnosis

                                                                                                                                                        60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                                                        Case Study 3 ndash Presentation

                                                                                                                                                        TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                                        PT 228 sec 113 ndash 146 sec

                                                                                                                                                        APTT 45 sec 25 ndash 34 sec

                                                                                                                                                        D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                                        Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                                        FV Normal 70-120

                                                                                                                                                        FVII Normal 55-170

                                                                                                                                                        FVIII Normal 60-150

                                                                                                                                                        Protein C Normal 70-130

                                                                                                                                                        Hb 134 gdL 14-16 gdL

                                                                                                                                                        WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                                        ALT 32 IUL 0ndash34 IUL

                                                                                                                                                        AST 28 IUL 0ndash34 IUL

                                                                                                                                                        BUN 09 mgdL 08-13 mgdL

                                                                                                                                                        Case Study 3 ndash Lab Results

                                                                                                                                                        Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                                        Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                                        Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                                        Case Study 4 ndash Presentation

                                                                                                                                                        TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                                        PT 28 sec 113 ndash 146 sec

                                                                                                                                                        APTT 71 sec 25 ndash 34 sec

                                                                                                                                                        D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                                        Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                                        FV Normal 70-120

                                                                                                                                                        FVII Normal 55-170

                                                                                                                                                        FVIII Normal 60-150

                                                                                                                                                        Protein C Normal 70-130

                                                                                                                                                        Hb 158 gdL 14-16 gdL

                                                                                                                                                        WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                                        ALT 60 IUL 0ndash34 IUL

                                                                                                                                                        AST 47 IUL 0ndash34 IUL

                                                                                                                                                        BUN 38 mgdL 08-13 mgdL

                                                                                                                                                        Case Study 4 ndash Lab Results

                                                                                                                                                        Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                                        Case Study 4 ndash Diagnosis

                                                                                                                                                        55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                                        Case Study 5 ndash Presentation

                                                                                                                                                        Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                        Case Study 5 ndash Lab Results and Time Course

                                                                                                                                                        Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                        TEST RESULT REFERENCE RANGE

                                                                                                                                                        Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                                        PT 215 sec 103 ndash 128 sec

                                                                                                                                                        APTT 44 sec 26 ndash 36 sec

                                                                                                                                                        D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                                        Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                                        FII FV FVIII Low Not reported (NR)

                                                                                                                                                        FVII FIX FX vWF Normal NR

                                                                                                                                                        Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                                        DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                                        dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                                        (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                                        (D) Illustration demonstrating repair

                                                                                                                                                        Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                                        Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                        29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                        Case Study 6 ndash Presentation

                                                                                                                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                        Case Study 6 ndash Lab Results

                                                                                                                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                        TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                        PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                        INR 658 1 ndash 125

                                                                                                                                                        APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                        D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                        Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                        Albumin 28 gdL NR

                                                                                                                                                        Hb 58 gdL NR

                                                                                                                                                        LDH 1196 UL NR

                                                                                                                                                        SGPT 144 IU NR

                                                                                                                                                        SGOT 88 IU NR

                                                                                                                                                        Bilirubin 32 mgdL NR

                                                                                                                                                        DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                        day postop

                                                                                                                                                        Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                        HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                        Case Study 6 ndash Discussion

                                                                                                                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                        44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                        Case Study 7 ndash Presentation

                                                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                        On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                        Case Study 7 ndash Presentation

                                                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                        Case Study 7 ndash Lab Results vs Time

                                                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                        Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                        Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                        On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                        Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                        DIC Take Home Messages

                                                                                                                                                        Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                        Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                        DIC

                                                                                                                                                        Thank you Questions

                                                                                                                                                        • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                        • Learning Objectives
                                                                                                                                                        • Slide Number 3
                                                                                                                                                        • Slide Number 4
                                                                                                                                                        • Slide Number 5
                                                                                                                                                        • Slide Number 6
                                                                                                                                                        • Slide Number 7
                                                                                                                                                        • Slide Number 8
                                                                                                                                                        • Wound Sealing
                                                                                                                                                        • The Three Steps of Hemostasis
                                                                                                                                                        • Vessel Wall
                                                                                                                                                        • Slide Number 12
                                                                                                                                                        • Slide Number 13
                                                                                                                                                        • Platelet Structure UnactivatedActivated
                                                                                                                                                        • Primary Hemostasis
                                                                                                                                                        • Primary Hemostasis Assays
                                                                                                                                                        • Slide Number 17
                                                                                                                                                        • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                        • Slide Number 19
                                                                                                                                                        • Coagulation factors
                                                                                                                                                        • Coagulation Assay Mechanisms
                                                                                                                                                        • Slide Number 22
                                                                                                                                                        • Fibrin Formation
                                                                                                                                                        • Slide Number 24
                                                                                                                                                        • Fibrinolysis Overview
                                                                                                                                                        • Fibrinolysis Overview
                                                                                                                                                        • Slide Number 27
                                                                                                                                                        • Fibrinolysis Releases D-dimers
                                                                                                                                                        • Basic Pathophysiology of DIC
                                                                                                                                                        • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                        • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                        • Clinical Conditions Associated With DIC
                                                                                                                                                        • Frequency of DIC in Selected Disease States
                                                                                                                                                        • Underlying Diseases in DIC Patients
                                                                                                                                                        • Slide Number 36
                                                                                                                                                        • Slide Number 37
                                                                                                                                                        • Slide Number 38
                                                                                                                                                        • Slide Number 39
                                                                                                                                                        • Pathophysiology of DIC
                                                                                                                                                        • Pathogenesis of DIC in Sepsis
                                                                                                                                                        • Host Response in Severe Sepsis
                                                                                                                                                        • Organ Failure in Severe Sepsis
                                                                                                                                                        • Mechanism of DIC in Organ Failure
                                                                                                                                                        • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                        • Slide Number 47
                                                                                                                                                        • Diverse and Opposing Effects of Thrombin
                                                                                                                                                        • Coagulation and Fibrinolysis in DIC
                                                                                                                                                        • Mechanism of DIC
                                                                                                                                                        • Pathophysiology of DIC
                                                                                                                                                        • Pathophysiology of DIC - Mechanism
                                                                                                                                                        • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                        • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                        • Pathophysiology of Overt DIC
                                                                                                                                                        • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                        • Slide Number 57
                                                                                                                                                        • Slide Number 58
                                                                                                                                                        • Slide Number 59
                                                                                                                                                        • Slide Number 60
                                                                                                                                                        • Slide Number 61
                                                                                                                                                        • BREAK
                                                                                                                                                        • Diagnostic and Management Approach for DIC
                                                                                                                                                        • Diagnosis of DIC
                                                                                                                                                        • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                        • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                        • Slide Number 67
                                                                                                                                                        • Slide Number 68
                                                                                                                                                        • British Journal of Haematology Overt DIC Score
                                                                                                                                                        • Slide Number 70
                                                                                                                                                        • Slide Number 71
                                                                                                                                                        • Slide Number 72
                                                                                                                                                        • Slide Number 73
                                                                                                                                                        • DIC Management Goals
                                                                                                                                                        • DIC Management and Treatment
                                                                                                                                                        • DIC Management Strategies
                                                                                                                                                        • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                        • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                        • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                        • D-dimer FDPs and DIC
                                                                                                                                                        • D-Dimer and FDPs in DIC
                                                                                                                                                        • Follow Up of DIC State of Disease
                                                                                                                                                        • FMD-Dimer in DIC Major Differences
                                                                                                                                                        • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                        • Slide Number 85
                                                                                                                                                        • Slide Number 86
                                                                                                                                                        • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                        • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                        • Slide Number 94
                                                                                                                                                        • Slide Number 95
                                                                                                                                                        • Slide Number 96
                                                                                                                                                        • Slide Number 97
                                                                                                                                                        • Slide Number 98
                                                                                                                                                        • Slide Number 99
                                                                                                                                                        • DIC Case Studies
                                                                                                                                                        • Case Study 1 - Presentation
                                                                                                                                                        • Case Study 1 ndash Lab Results
                                                                                                                                                        • Case Study 1 ndash Microscopy
                                                                                                                                                        • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                        • Slide Number 105
                                                                                                                                                        • Slide Number 106
                                                                                                                                                        • Slide Number 107
                                                                                                                                                        • Slide Number 108
                                                                                                                                                        • Slide Number 109
                                                                                                                                                        • Slide Number 110
                                                                                                                                                        • Slide Number 111
                                                                                                                                                        • Slide Number 112
                                                                                                                                                        • Slide Number 113
                                                                                                                                                        • Slide Number 114
                                                                                                                                                        • Slide Number 115
                                                                                                                                                        • Slide Number 116
                                                                                                                                                        • Slide Number 117
                                                                                                                                                        • Slide Number 118
                                                                                                                                                        • Slide Number 119
                                                                                                                                                        • Slide Number 120
                                                                                                                                                        • Slide Number 121
                                                                                                                                                        • Slide Number 122
                                                                                                                                                        • Slide Number 123
                                                                                                                                                        • Slide Number 124
                                                                                                                                                        • Slide Number 125
                                                                                                                                                        • DIC Take Home Messages
                                                                                                                                                        • Slide Number 127
                                                                                                                                                        • Slide Number 128

                                                                                                                                                          Anticoagulant Factor Concentrate Treatment

                                                                                                                                                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                                                          Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis

                                                                                                                                                          Anticoagulant Factor Concentrate Treatment Trials

                                                                                                                                                          Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                                                          Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                                                                                                          Markers of Thrombin amp Plasmin Generation in DIC

                                                                                                                                                          D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                                                                                                          Cut-off value

                                                                                                                                                          Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                                                                                                          degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                                                                                                          D-dimer FDPs and DIC

                                                                                                                                                          D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                                                                                                          Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                                                                                                          Follow Up of DIC State of Disease

                                                                                                                                                          Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                                                                                                          Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                                                                                                          FMD-Dimer in DIC Major Differences

                                                                                                                                                          onset of thrombosis

                                                                                                                                                          days

                                                                                                                                                          Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                                                                                                          FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                                                                                                          D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                                                                                                          of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                                                                                                          0

                                                                                                                                                          20

                                                                                                                                                          40

                                                                                                                                                          60

                                                                                                                                                          80

                                                                                                                                                          100

                                                                                                                                                          94 85 90N = 62

                                                                                                                                                          Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                                                                                                          Positivity of Test Results ISTH Score and Disease State

                                                                                                                                                          Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                                          Red bar positive for 2 points of DIC score

                                                                                                                                                          Pink bar positive for 1-2 points of DIC score

                                                                                                                                                          HT hematopoietic tumor

                                                                                                                                                          IF infection

                                                                                                                                                          SC solid cancer

                                                                                                                                                          Markers in Patients with or without DIC

                                                                                                                                                          Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                                          HT hematopoietic tumorIF infectionSC solid cancer

                                                                                                                                                          Comparing an Automated FM vs Manual FSP Test

                                                                                                                                                          Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                                                                                          Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                                                                                          Automated (Mitsubishi) vs Automated (Stago)

                                                                                                                                                          In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                                                                                          Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                          In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                          In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                          In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                          Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                          No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                                                                          Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                          Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                          Non Overt DIC Overt DIC

                                                                                                                                                          AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                                                                          Trends in Markers of DIC for Different Patients

                                                                                                                                                          Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                                                                          Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                                                                          Trends in Markers of DIC for Different Patients

                                                                                                                                                          Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                          FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                                                                          28 day outcome survival

                                                                                                                                                          28 day outcome death

                                                                                                                                                          Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                          Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                          Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                                                                          Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                          Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                          Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                                                                          DIC Case Studies

                                                                                                                                                          Case Study 1 - Presentation

                                                                                                                                                          18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                                                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                          Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                                                          WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                                                          RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                                                          Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                                                          Hematocrit 195 401 ndash 510

                                                                                                                                                          MCV 95 fL 790 ndash 922 fL

                                                                                                                                                          MPV 12 fL 94 ndash 124 fL

                                                                                                                                                          Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                                                          Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                                                          Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                                                          PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                                                          APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                                                          Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                                                          D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                                                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                          Case Study 1 ndash Microscopy

                                                                                                                                                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                          Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                                                          Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                                                          DIC due to TF release by APL blasts

                                                                                                                                                          Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                                                          Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                                                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                          20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                                                          Case Study 2 ndash Presentation

                                                                                                                                                          TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                                                          PT 30 sec 113 ndash 146 sec

                                                                                                                                                          APTT 75 sec 25 ndash 34 sec

                                                                                                                                                          D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                                                          Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                                                          pH 728 738 to 742

                                                                                                                                                          PaO2 570 mmHg 80-100 mmHg

                                                                                                                                                          WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                                                          ALT 111 IUL 0ndash34 IUL

                                                                                                                                                          AST 61 IUL 0ndash34 IUL

                                                                                                                                                          BUN 303 mgdL 08-13 mgdL

                                                                                                                                                          Case Study 2 ndash Lab Results

                                                                                                                                                          Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                                                          Case Study 2 ndash Diagnosis

                                                                                                                                                          60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                                                          Case Study 3 ndash Presentation

                                                                                                                                                          TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                                          PT 228 sec 113 ndash 146 sec

                                                                                                                                                          APTT 45 sec 25 ndash 34 sec

                                                                                                                                                          D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                                          Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                                          FV Normal 70-120

                                                                                                                                                          FVII Normal 55-170

                                                                                                                                                          FVIII Normal 60-150

                                                                                                                                                          Protein C Normal 70-130

                                                                                                                                                          Hb 134 gdL 14-16 gdL

                                                                                                                                                          WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                                          ALT 32 IUL 0ndash34 IUL

                                                                                                                                                          AST 28 IUL 0ndash34 IUL

                                                                                                                                                          BUN 09 mgdL 08-13 mgdL

                                                                                                                                                          Case Study 3 ndash Lab Results

                                                                                                                                                          Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                                          Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                                          Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                                          Case Study 4 ndash Presentation

                                                                                                                                                          TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                                          PT 28 sec 113 ndash 146 sec

                                                                                                                                                          APTT 71 sec 25 ndash 34 sec

                                                                                                                                                          D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                                          Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                                          FV Normal 70-120

                                                                                                                                                          FVII Normal 55-170

                                                                                                                                                          FVIII Normal 60-150

                                                                                                                                                          Protein C Normal 70-130

                                                                                                                                                          Hb 158 gdL 14-16 gdL

                                                                                                                                                          WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                                          ALT 60 IUL 0ndash34 IUL

                                                                                                                                                          AST 47 IUL 0ndash34 IUL

                                                                                                                                                          BUN 38 mgdL 08-13 mgdL

                                                                                                                                                          Case Study 4 ndash Lab Results

                                                                                                                                                          Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                                          Case Study 4 ndash Diagnosis

                                                                                                                                                          55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                                          Case Study 5 ndash Presentation

                                                                                                                                                          Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                          Case Study 5 ndash Lab Results and Time Course

                                                                                                                                                          Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                          TEST RESULT REFERENCE RANGE

                                                                                                                                                          Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                                          PT 215 sec 103 ndash 128 sec

                                                                                                                                                          APTT 44 sec 26 ndash 36 sec

                                                                                                                                                          D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                                          Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                                          FII FV FVIII Low Not reported (NR)

                                                                                                                                                          FVII FIX FX vWF Normal NR

                                                                                                                                                          Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                                          DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                                          dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                                          (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                                          (D) Illustration demonstrating repair

                                                                                                                                                          Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                                          Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                          29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                          Case Study 6 ndash Presentation

                                                                                                                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                          Case Study 6 ndash Lab Results

                                                                                                                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                          TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                          PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                          INR 658 1 ndash 125

                                                                                                                                                          APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                          D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                          Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                          Albumin 28 gdL NR

                                                                                                                                                          Hb 58 gdL NR

                                                                                                                                                          LDH 1196 UL NR

                                                                                                                                                          SGPT 144 IU NR

                                                                                                                                                          SGOT 88 IU NR

                                                                                                                                                          Bilirubin 32 mgdL NR

                                                                                                                                                          DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                          day postop

                                                                                                                                                          Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                          HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                          Case Study 6 ndash Discussion

                                                                                                                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                          44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                          Case Study 7 ndash Presentation

                                                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                          On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                          Case Study 7 ndash Presentation

                                                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                          Case Study 7 ndash Lab Results vs Time

                                                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                          Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                          Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                          On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                          Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                          DIC Take Home Messages

                                                                                                                                                          Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                          Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                          DIC

                                                                                                                                                          Thank you Questions

                                                                                                                                                          • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                          • Learning Objectives
                                                                                                                                                          • Slide Number 3
                                                                                                                                                          • Slide Number 4
                                                                                                                                                          • Slide Number 5
                                                                                                                                                          • Slide Number 6
                                                                                                                                                          • Slide Number 7
                                                                                                                                                          • Slide Number 8
                                                                                                                                                          • Wound Sealing
                                                                                                                                                          • The Three Steps of Hemostasis
                                                                                                                                                          • Vessel Wall
                                                                                                                                                          • Slide Number 12
                                                                                                                                                          • Slide Number 13
                                                                                                                                                          • Platelet Structure UnactivatedActivated
                                                                                                                                                          • Primary Hemostasis
                                                                                                                                                          • Primary Hemostasis Assays
                                                                                                                                                          • Slide Number 17
                                                                                                                                                          • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                          • Slide Number 19
                                                                                                                                                          • Coagulation factors
                                                                                                                                                          • Coagulation Assay Mechanisms
                                                                                                                                                          • Slide Number 22
                                                                                                                                                          • Fibrin Formation
                                                                                                                                                          • Slide Number 24
                                                                                                                                                          • Fibrinolysis Overview
                                                                                                                                                          • Fibrinolysis Overview
                                                                                                                                                          • Slide Number 27
                                                                                                                                                          • Fibrinolysis Releases D-dimers
                                                                                                                                                          • Basic Pathophysiology of DIC
                                                                                                                                                          • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                          • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                          • Clinical Conditions Associated With DIC
                                                                                                                                                          • Frequency of DIC in Selected Disease States
                                                                                                                                                          • Underlying Diseases in DIC Patients
                                                                                                                                                          • Slide Number 36
                                                                                                                                                          • Slide Number 37
                                                                                                                                                          • Slide Number 38
                                                                                                                                                          • Slide Number 39
                                                                                                                                                          • Pathophysiology of DIC
                                                                                                                                                          • Pathogenesis of DIC in Sepsis
                                                                                                                                                          • Host Response in Severe Sepsis
                                                                                                                                                          • Organ Failure in Severe Sepsis
                                                                                                                                                          • Mechanism of DIC in Organ Failure
                                                                                                                                                          • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                          • Slide Number 47
                                                                                                                                                          • Diverse and Opposing Effects of Thrombin
                                                                                                                                                          • Coagulation and Fibrinolysis in DIC
                                                                                                                                                          • Mechanism of DIC
                                                                                                                                                          • Pathophysiology of DIC
                                                                                                                                                          • Pathophysiology of DIC - Mechanism
                                                                                                                                                          • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                          • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                          • Pathophysiology of Overt DIC
                                                                                                                                                          • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                          • Slide Number 57
                                                                                                                                                          • Slide Number 58
                                                                                                                                                          • Slide Number 59
                                                                                                                                                          • Slide Number 60
                                                                                                                                                          • Slide Number 61
                                                                                                                                                          • BREAK
                                                                                                                                                          • Diagnostic and Management Approach for DIC
                                                                                                                                                          • Diagnosis of DIC
                                                                                                                                                          • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                          • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                          • Slide Number 67
                                                                                                                                                          • Slide Number 68
                                                                                                                                                          • British Journal of Haematology Overt DIC Score
                                                                                                                                                          • Slide Number 70
                                                                                                                                                          • Slide Number 71
                                                                                                                                                          • Slide Number 72
                                                                                                                                                          • Slide Number 73
                                                                                                                                                          • DIC Management Goals
                                                                                                                                                          • DIC Management and Treatment
                                                                                                                                                          • DIC Management Strategies
                                                                                                                                                          • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                          • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                          • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                          • D-dimer FDPs and DIC
                                                                                                                                                          • D-Dimer and FDPs in DIC
                                                                                                                                                          • Follow Up of DIC State of Disease
                                                                                                                                                          • FMD-Dimer in DIC Major Differences
                                                                                                                                                          • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                          • Slide Number 85
                                                                                                                                                          • Slide Number 86
                                                                                                                                                          • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                          • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                          • Slide Number 94
                                                                                                                                                          • Slide Number 95
                                                                                                                                                          • Slide Number 96
                                                                                                                                                          • Slide Number 97
                                                                                                                                                          • Slide Number 98
                                                                                                                                                          • Slide Number 99
                                                                                                                                                          • DIC Case Studies
                                                                                                                                                          • Case Study 1 - Presentation
                                                                                                                                                          • Case Study 1 ndash Lab Results
                                                                                                                                                          • Case Study 1 ndash Microscopy
                                                                                                                                                          • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                          • Slide Number 105
                                                                                                                                                          • Slide Number 106
                                                                                                                                                          • Slide Number 107
                                                                                                                                                          • Slide Number 108
                                                                                                                                                          • Slide Number 109
                                                                                                                                                          • Slide Number 110
                                                                                                                                                          • Slide Number 111
                                                                                                                                                          • Slide Number 112
                                                                                                                                                          • Slide Number 113
                                                                                                                                                          • Slide Number 114
                                                                                                                                                          • Slide Number 115
                                                                                                                                                          • Slide Number 116
                                                                                                                                                          • Slide Number 117
                                                                                                                                                          • Slide Number 118
                                                                                                                                                          • Slide Number 119
                                                                                                                                                          • Slide Number 120
                                                                                                                                                          • Slide Number 121
                                                                                                                                                          • Slide Number 122
                                                                                                                                                          • Slide Number 123
                                                                                                                                                          • Slide Number 124
                                                                                                                                                          • Slide Number 125
                                                                                                                                                          • DIC Take Home Messages
                                                                                                                                                          • Slide Number 127
                                                                                                                                                          • Slide Number 128

                                                                                                                                                            Anticoagulant Factor Concentrate Treatment Trials

                                                                                                                                                            Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037

                                                                                                                                                            Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise

                                                                                                                                                            Markers of Thrombin amp Plasmin Generation in DIC

                                                                                                                                                            D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                                                                                                            Cut-off value

                                                                                                                                                            Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                                                                                                            degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                                                                                                            D-dimer FDPs and DIC

                                                                                                                                                            D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                                                                                                            Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                                                                                                            Follow Up of DIC State of Disease

                                                                                                                                                            Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                                                                                                            Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                                                                                                            FMD-Dimer in DIC Major Differences

                                                                                                                                                            onset of thrombosis

                                                                                                                                                            days

                                                                                                                                                            Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                                                                                                            FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                                                                                                            D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                                                                                                            of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                                                                                                            0

                                                                                                                                                            20

                                                                                                                                                            40

                                                                                                                                                            60

                                                                                                                                                            80

                                                                                                                                                            100

                                                                                                                                                            94 85 90N = 62

                                                                                                                                                            Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                                                                                                            Positivity of Test Results ISTH Score and Disease State

                                                                                                                                                            Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                                            Red bar positive for 2 points of DIC score

                                                                                                                                                            Pink bar positive for 1-2 points of DIC score

                                                                                                                                                            HT hematopoietic tumor

                                                                                                                                                            IF infection

                                                                                                                                                            SC solid cancer

                                                                                                                                                            Markers in Patients with or without DIC

                                                                                                                                                            Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                                            HT hematopoietic tumorIF infectionSC solid cancer

                                                                                                                                                            Comparing an Automated FM vs Manual FSP Test

                                                                                                                                                            Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                                                                                            Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                                                                                            Automated (Mitsubishi) vs Automated (Stago)

                                                                                                                                                            In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                                                                                            Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                            In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                            In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                            In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                            Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                            No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                                                                            Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                            Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                            Non Overt DIC Overt DIC

                                                                                                                                                            AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                                                                            Trends in Markers of DIC for Different Patients

                                                                                                                                                            Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                                                                            Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                                                                            Trends in Markers of DIC for Different Patients

                                                                                                                                                            Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                            FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                                                                            28 day outcome survival

                                                                                                                                                            28 day outcome death

                                                                                                                                                            Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                            Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                            Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                                                                            Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                            Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                            Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                                                                            DIC Case Studies

                                                                                                                                                            Case Study 1 - Presentation

                                                                                                                                                            18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                                                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                            Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                                                            WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                                                            RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                                                            Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                                                            Hematocrit 195 401 ndash 510

                                                                                                                                                            MCV 95 fL 790 ndash 922 fL

                                                                                                                                                            MPV 12 fL 94 ndash 124 fL

                                                                                                                                                            Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                                                            Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                                                            Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                                                            PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                                                            APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                                                            Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                                                            D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                                                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                            Case Study 1 ndash Microscopy

                                                                                                                                                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                            Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                                                            Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                                                            DIC due to TF release by APL blasts

                                                                                                                                                            Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                                                            Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                                                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                            20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                                                            Case Study 2 ndash Presentation

                                                                                                                                                            TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                                                            PT 30 sec 113 ndash 146 sec

                                                                                                                                                            APTT 75 sec 25 ndash 34 sec

                                                                                                                                                            D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                                                            Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                                                            pH 728 738 to 742

                                                                                                                                                            PaO2 570 mmHg 80-100 mmHg

                                                                                                                                                            WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                                                            ALT 111 IUL 0ndash34 IUL

                                                                                                                                                            AST 61 IUL 0ndash34 IUL

                                                                                                                                                            BUN 303 mgdL 08-13 mgdL

                                                                                                                                                            Case Study 2 ndash Lab Results

                                                                                                                                                            Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                                                            Case Study 2 ndash Diagnosis

                                                                                                                                                            60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                                                            Case Study 3 ndash Presentation

                                                                                                                                                            TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                                            PT 228 sec 113 ndash 146 sec

                                                                                                                                                            APTT 45 sec 25 ndash 34 sec

                                                                                                                                                            D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                                            Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                                            FV Normal 70-120

                                                                                                                                                            FVII Normal 55-170

                                                                                                                                                            FVIII Normal 60-150

                                                                                                                                                            Protein C Normal 70-130

                                                                                                                                                            Hb 134 gdL 14-16 gdL

                                                                                                                                                            WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                                            ALT 32 IUL 0ndash34 IUL

                                                                                                                                                            AST 28 IUL 0ndash34 IUL

                                                                                                                                                            BUN 09 mgdL 08-13 mgdL

                                                                                                                                                            Case Study 3 ndash Lab Results

                                                                                                                                                            Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                                            Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                                            Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                                            Case Study 4 ndash Presentation

                                                                                                                                                            TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                                            PT 28 sec 113 ndash 146 sec

                                                                                                                                                            APTT 71 sec 25 ndash 34 sec

                                                                                                                                                            D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                                            Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                                            FV Normal 70-120

                                                                                                                                                            FVII Normal 55-170

                                                                                                                                                            FVIII Normal 60-150

                                                                                                                                                            Protein C Normal 70-130

                                                                                                                                                            Hb 158 gdL 14-16 gdL

                                                                                                                                                            WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                                            ALT 60 IUL 0ndash34 IUL

                                                                                                                                                            AST 47 IUL 0ndash34 IUL

                                                                                                                                                            BUN 38 mgdL 08-13 mgdL

                                                                                                                                                            Case Study 4 ndash Lab Results

                                                                                                                                                            Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                                            Case Study 4 ndash Diagnosis

                                                                                                                                                            55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                                            Case Study 5 ndash Presentation

                                                                                                                                                            Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                            Case Study 5 ndash Lab Results and Time Course

                                                                                                                                                            Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                            TEST RESULT REFERENCE RANGE

                                                                                                                                                            Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                                            PT 215 sec 103 ndash 128 sec

                                                                                                                                                            APTT 44 sec 26 ndash 36 sec

                                                                                                                                                            D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                                            Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                                            FII FV FVIII Low Not reported (NR)

                                                                                                                                                            FVII FIX FX vWF Normal NR

                                                                                                                                                            Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                                            DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                                            dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                                            (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                                            (D) Illustration demonstrating repair

                                                                                                                                                            Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                                            Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                            29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                            Case Study 6 ndash Presentation

                                                                                                                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                            Case Study 6 ndash Lab Results

                                                                                                                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                            TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                            PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                            INR 658 1 ndash 125

                                                                                                                                                            APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                            D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                            Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                            Albumin 28 gdL NR

                                                                                                                                                            Hb 58 gdL NR

                                                                                                                                                            LDH 1196 UL NR

                                                                                                                                                            SGPT 144 IU NR

                                                                                                                                                            SGOT 88 IU NR

                                                                                                                                                            Bilirubin 32 mgdL NR

                                                                                                                                                            DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                            day postop

                                                                                                                                                            Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                            HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                            Case Study 6 ndash Discussion

                                                                                                                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                            44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                            Case Study 7 ndash Presentation

                                                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                            On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                            Case Study 7 ndash Presentation

                                                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                            Case Study 7 ndash Lab Results vs Time

                                                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                            Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                            Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                            On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                            Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                            DIC Take Home Messages

                                                                                                                                                            Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                            Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                            DIC

                                                                                                                                                            Thank you Questions

                                                                                                                                                            • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                            • Learning Objectives
                                                                                                                                                            • Slide Number 3
                                                                                                                                                            • Slide Number 4
                                                                                                                                                            • Slide Number 5
                                                                                                                                                            • Slide Number 6
                                                                                                                                                            • Slide Number 7
                                                                                                                                                            • Slide Number 8
                                                                                                                                                            • Wound Sealing
                                                                                                                                                            • The Three Steps of Hemostasis
                                                                                                                                                            • Vessel Wall
                                                                                                                                                            • Slide Number 12
                                                                                                                                                            • Slide Number 13
                                                                                                                                                            • Platelet Structure UnactivatedActivated
                                                                                                                                                            • Primary Hemostasis
                                                                                                                                                            • Primary Hemostasis Assays
                                                                                                                                                            • Slide Number 17
                                                                                                                                                            • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                            • Slide Number 19
                                                                                                                                                            • Coagulation factors
                                                                                                                                                            • Coagulation Assay Mechanisms
                                                                                                                                                            • Slide Number 22
                                                                                                                                                            • Fibrin Formation
                                                                                                                                                            • Slide Number 24
                                                                                                                                                            • Fibrinolysis Overview
                                                                                                                                                            • Fibrinolysis Overview
                                                                                                                                                            • Slide Number 27
                                                                                                                                                            • Fibrinolysis Releases D-dimers
                                                                                                                                                            • Basic Pathophysiology of DIC
                                                                                                                                                            • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                            • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                            • Clinical Conditions Associated With DIC
                                                                                                                                                            • Frequency of DIC in Selected Disease States
                                                                                                                                                            • Underlying Diseases in DIC Patients
                                                                                                                                                            • Slide Number 36
                                                                                                                                                            • Slide Number 37
                                                                                                                                                            • Slide Number 38
                                                                                                                                                            • Slide Number 39
                                                                                                                                                            • Pathophysiology of DIC
                                                                                                                                                            • Pathogenesis of DIC in Sepsis
                                                                                                                                                            • Host Response in Severe Sepsis
                                                                                                                                                            • Organ Failure in Severe Sepsis
                                                                                                                                                            • Mechanism of DIC in Organ Failure
                                                                                                                                                            • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                            • Slide Number 47
                                                                                                                                                            • Diverse and Opposing Effects of Thrombin
                                                                                                                                                            • Coagulation and Fibrinolysis in DIC
                                                                                                                                                            • Mechanism of DIC
                                                                                                                                                            • Pathophysiology of DIC
                                                                                                                                                            • Pathophysiology of DIC - Mechanism
                                                                                                                                                            • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                            • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                            • Pathophysiology of Overt DIC
                                                                                                                                                            • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                            • Slide Number 57
                                                                                                                                                            • Slide Number 58
                                                                                                                                                            • Slide Number 59
                                                                                                                                                            • Slide Number 60
                                                                                                                                                            • Slide Number 61
                                                                                                                                                            • BREAK
                                                                                                                                                            • Diagnostic and Management Approach for DIC
                                                                                                                                                            • Diagnosis of DIC
                                                                                                                                                            • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                            • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                            • Slide Number 67
                                                                                                                                                            • Slide Number 68
                                                                                                                                                            • British Journal of Haematology Overt DIC Score
                                                                                                                                                            • Slide Number 70
                                                                                                                                                            • Slide Number 71
                                                                                                                                                            • Slide Number 72
                                                                                                                                                            • Slide Number 73
                                                                                                                                                            • DIC Management Goals
                                                                                                                                                            • DIC Management and Treatment
                                                                                                                                                            • DIC Management Strategies
                                                                                                                                                            • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                            • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                            • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                            • D-dimer FDPs and DIC
                                                                                                                                                            • D-Dimer and FDPs in DIC
                                                                                                                                                            • Follow Up of DIC State of Disease
                                                                                                                                                            • FMD-Dimer in DIC Major Differences
                                                                                                                                                            • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                            • Slide Number 85
                                                                                                                                                            • Slide Number 86
                                                                                                                                                            • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                            • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                            • Slide Number 94
                                                                                                                                                            • Slide Number 95
                                                                                                                                                            • Slide Number 96
                                                                                                                                                            • Slide Number 97
                                                                                                                                                            • Slide Number 98
                                                                                                                                                            • Slide Number 99
                                                                                                                                                            • DIC Case Studies
                                                                                                                                                            • Case Study 1 - Presentation
                                                                                                                                                            • Case Study 1 ndash Lab Results
                                                                                                                                                            • Case Study 1 ndash Microscopy
                                                                                                                                                            • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                            • Slide Number 105
                                                                                                                                                            • Slide Number 106
                                                                                                                                                            • Slide Number 107
                                                                                                                                                            • Slide Number 108
                                                                                                                                                            • Slide Number 109
                                                                                                                                                            • Slide Number 110
                                                                                                                                                            • Slide Number 111
                                                                                                                                                            • Slide Number 112
                                                                                                                                                            • Slide Number 113
                                                                                                                                                            • Slide Number 114
                                                                                                                                                            • Slide Number 115
                                                                                                                                                            • Slide Number 116
                                                                                                                                                            • Slide Number 117
                                                                                                                                                            • Slide Number 118
                                                                                                                                                            • Slide Number 119
                                                                                                                                                            • Slide Number 120
                                                                                                                                                            • Slide Number 121
                                                                                                                                                            • Slide Number 122
                                                                                                                                                            • Slide Number 123
                                                                                                                                                            • Slide Number 124
                                                                                                                                                            • Slide Number 125
                                                                                                                                                            • DIC Take Home Messages
                                                                                                                                                            • Slide Number 127
                                                                                                                                                            • Slide Number 128

                                                                                                                                                              Markers of Thrombin amp Plasmin Generation in DIC

                                                                                                                                                              D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                                                                                                              Cut-off value

                                                                                                                                                              Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                                                                                                              degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                                                                                                              D-dimer FDPs and DIC

                                                                                                                                                              D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                                                                                                              Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                                                                                                              Follow Up of DIC State of Disease

                                                                                                                                                              Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                                                                                                              Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                                                                                                              FMD-Dimer in DIC Major Differences

                                                                                                                                                              onset of thrombosis

                                                                                                                                                              days

                                                                                                                                                              Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                                                                                                              FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                                                                                                              D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                                                                                                              of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                                                                                                              0

                                                                                                                                                              20

                                                                                                                                                              40

                                                                                                                                                              60

                                                                                                                                                              80

                                                                                                                                                              100

                                                                                                                                                              94 85 90N = 62

                                                                                                                                                              Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                                                                                                              Positivity of Test Results ISTH Score and Disease State

                                                                                                                                                              Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                                              Red bar positive for 2 points of DIC score

                                                                                                                                                              Pink bar positive for 1-2 points of DIC score

                                                                                                                                                              HT hematopoietic tumor

                                                                                                                                                              IF infection

                                                                                                                                                              SC solid cancer

                                                                                                                                                              Markers in Patients with or without DIC

                                                                                                                                                              Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                                              HT hematopoietic tumorIF infectionSC solid cancer

                                                                                                                                                              Comparing an Automated FM vs Manual FSP Test

                                                                                                                                                              Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                                                                                              Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                                                                                              Automated (Mitsubishi) vs Automated (Stago)

                                                                                                                                                              In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                                                                                              Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                              In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                              In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                              In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                              Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                              No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                                                                              Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                              Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                              Non Overt DIC Overt DIC

                                                                                                                                                              AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                                                                              Trends in Markers of DIC for Different Patients

                                                                                                                                                              Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                                                                              Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                                                                              Trends in Markers of DIC for Different Patients

                                                                                                                                                              Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                              FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                                                                              28 day outcome survival

                                                                                                                                                              28 day outcome death

                                                                                                                                                              Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                              Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                              Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                                                                              Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                              Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                              Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                                                                              DIC Case Studies

                                                                                                                                                              Case Study 1 - Presentation

                                                                                                                                                              18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                                                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                              Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                                                              WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                                                              RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                                                              Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                                                              Hematocrit 195 401 ndash 510

                                                                                                                                                              MCV 95 fL 790 ndash 922 fL

                                                                                                                                                              MPV 12 fL 94 ndash 124 fL

                                                                                                                                                              Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                                                              Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                                                              Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                                                              PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                                                              APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                                                              Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                                                              D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                                                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                              Case Study 1 ndash Microscopy

                                                                                                                                                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                              Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                                                              Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                                                              DIC due to TF release by APL blasts

                                                                                                                                                              Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                                                              Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                                                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                              20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                                                              Case Study 2 ndash Presentation

                                                                                                                                                              TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                                                              PT 30 sec 113 ndash 146 sec

                                                                                                                                                              APTT 75 sec 25 ndash 34 sec

                                                                                                                                                              D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                                                              Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                                                              pH 728 738 to 742

                                                                                                                                                              PaO2 570 mmHg 80-100 mmHg

                                                                                                                                                              WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                                                              ALT 111 IUL 0ndash34 IUL

                                                                                                                                                              AST 61 IUL 0ndash34 IUL

                                                                                                                                                              BUN 303 mgdL 08-13 mgdL

                                                                                                                                                              Case Study 2 ndash Lab Results

                                                                                                                                                              Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                                                              Case Study 2 ndash Diagnosis

                                                                                                                                                              60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                                                              Case Study 3 ndash Presentation

                                                                                                                                                              TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                                              PT 228 sec 113 ndash 146 sec

                                                                                                                                                              APTT 45 sec 25 ndash 34 sec

                                                                                                                                                              D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                                              Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                                              FV Normal 70-120

                                                                                                                                                              FVII Normal 55-170

                                                                                                                                                              FVIII Normal 60-150

                                                                                                                                                              Protein C Normal 70-130

                                                                                                                                                              Hb 134 gdL 14-16 gdL

                                                                                                                                                              WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                                              ALT 32 IUL 0ndash34 IUL

                                                                                                                                                              AST 28 IUL 0ndash34 IUL

                                                                                                                                                              BUN 09 mgdL 08-13 mgdL

                                                                                                                                                              Case Study 3 ndash Lab Results

                                                                                                                                                              Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                                              Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                                              Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                                              Case Study 4 ndash Presentation

                                                                                                                                                              TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                                              PT 28 sec 113 ndash 146 sec

                                                                                                                                                              APTT 71 sec 25 ndash 34 sec

                                                                                                                                                              D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                                              Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                                              FV Normal 70-120

                                                                                                                                                              FVII Normal 55-170

                                                                                                                                                              FVIII Normal 60-150

                                                                                                                                                              Protein C Normal 70-130

                                                                                                                                                              Hb 158 gdL 14-16 gdL

                                                                                                                                                              WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                                              ALT 60 IUL 0ndash34 IUL

                                                                                                                                                              AST 47 IUL 0ndash34 IUL

                                                                                                                                                              BUN 38 mgdL 08-13 mgdL

                                                                                                                                                              Case Study 4 ndash Lab Results

                                                                                                                                                              Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                                              Case Study 4 ndash Diagnosis

                                                                                                                                                              55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                                              Case Study 5 ndash Presentation

                                                                                                                                                              Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                              Case Study 5 ndash Lab Results and Time Course

                                                                                                                                                              Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                              TEST RESULT REFERENCE RANGE

                                                                                                                                                              Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                                              PT 215 sec 103 ndash 128 sec

                                                                                                                                                              APTT 44 sec 26 ndash 36 sec

                                                                                                                                                              D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                                              Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                                              FII FV FVIII Low Not reported (NR)

                                                                                                                                                              FVII FIX FX vWF Normal NR

                                                                                                                                                              Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                                              DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                                              dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                                              (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                                              (D) Illustration demonstrating repair

                                                                                                                                                              Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                                              Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                              29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                              Case Study 6 ndash Presentation

                                                                                                                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                              Case Study 6 ndash Lab Results

                                                                                                                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                              TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                              PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                              INR 658 1 ndash 125

                                                                                                                                                              APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                              D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                              Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                              Albumin 28 gdL NR

                                                                                                                                                              Hb 58 gdL NR

                                                                                                                                                              LDH 1196 UL NR

                                                                                                                                                              SGPT 144 IU NR

                                                                                                                                                              SGOT 88 IU NR

                                                                                                                                                              Bilirubin 32 mgdL NR

                                                                                                                                                              DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                              day postop

                                                                                                                                                              Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                              HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                              Case Study 6 ndash Discussion

                                                                                                                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                              44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                              Case Study 7 ndash Presentation

                                                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                              On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                              Case Study 7 ndash Presentation

                                                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                              Case Study 7 ndash Lab Results vs Time

                                                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                              Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                              Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                              On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                              Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                              DIC Take Home Messages

                                                                                                                                                              Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                              Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                              DIC

                                                                                                                                                              Thank you Questions

                                                                                                                                                              • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                              • Learning Objectives
                                                                                                                                                              • Slide Number 3
                                                                                                                                                              • Slide Number 4
                                                                                                                                                              • Slide Number 5
                                                                                                                                                              • Slide Number 6
                                                                                                                                                              • Slide Number 7
                                                                                                                                                              • Slide Number 8
                                                                                                                                                              • Wound Sealing
                                                                                                                                                              • The Three Steps of Hemostasis
                                                                                                                                                              • Vessel Wall
                                                                                                                                                              • Slide Number 12
                                                                                                                                                              • Slide Number 13
                                                                                                                                                              • Platelet Structure UnactivatedActivated
                                                                                                                                                              • Primary Hemostasis
                                                                                                                                                              • Primary Hemostasis Assays
                                                                                                                                                              • Slide Number 17
                                                                                                                                                              • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                              • Slide Number 19
                                                                                                                                                              • Coagulation factors
                                                                                                                                                              • Coagulation Assay Mechanisms
                                                                                                                                                              • Slide Number 22
                                                                                                                                                              • Fibrin Formation
                                                                                                                                                              • Slide Number 24
                                                                                                                                                              • Fibrinolysis Overview
                                                                                                                                                              • Fibrinolysis Overview
                                                                                                                                                              • Slide Number 27
                                                                                                                                                              • Fibrinolysis Releases D-dimers
                                                                                                                                                              • Basic Pathophysiology of DIC
                                                                                                                                                              • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                              • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                              • Clinical Conditions Associated With DIC
                                                                                                                                                              • Frequency of DIC in Selected Disease States
                                                                                                                                                              • Underlying Diseases in DIC Patients
                                                                                                                                                              • Slide Number 36
                                                                                                                                                              • Slide Number 37
                                                                                                                                                              • Slide Number 38
                                                                                                                                                              • Slide Number 39
                                                                                                                                                              • Pathophysiology of DIC
                                                                                                                                                              • Pathogenesis of DIC in Sepsis
                                                                                                                                                              • Host Response in Severe Sepsis
                                                                                                                                                              • Organ Failure in Severe Sepsis
                                                                                                                                                              • Mechanism of DIC in Organ Failure
                                                                                                                                                              • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                              • Slide Number 47
                                                                                                                                                              • Diverse and Opposing Effects of Thrombin
                                                                                                                                                              • Coagulation and Fibrinolysis in DIC
                                                                                                                                                              • Mechanism of DIC
                                                                                                                                                              • Pathophysiology of DIC
                                                                                                                                                              • Pathophysiology of DIC - Mechanism
                                                                                                                                                              • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                              • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                              • Pathophysiology of Overt DIC
                                                                                                                                                              • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                              • Slide Number 57
                                                                                                                                                              • Slide Number 58
                                                                                                                                                              • Slide Number 59
                                                                                                                                                              • Slide Number 60
                                                                                                                                                              • Slide Number 61
                                                                                                                                                              • BREAK
                                                                                                                                                              • Diagnostic and Management Approach for DIC
                                                                                                                                                              • Diagnosis of DIC
                                                                                                                                                              • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                              • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                              • Slide Number 67
                                                                                                                                                              • Slide Number 68
                                                                                                                                                              • British Journal of Haematology Overt DIC Score
                                                                                                                                                              • Slide Number 70
                                                                                                                                                              • Slide Number 71
                                                                                                                                                              • Slide Number 72
                                                                                                                                                              • Slide Number 73
                                                                                                                                                              • DIC Management Goals
                                                                                                                                                              • DIC Management and Treatment
                                                                                                                                                              • DIC Management Strategies
                                                                                                                                                              • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                              • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                              • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                              • D-dimer FDPs and DIC
                                                                                                                                                              • D-Dimer and FDPs in DIC
                                                                                                                                                              • Follow Up of DIC State of Disease
                                                                                                                                                              • FMD-Dimer in DIC Major Differences
                                                                                                                                                              • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                              • Slide Number 85
                                                                                                                                                              • Slide Number 86
                                                                                                                                                              • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                              • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                              • Slide Number 94
                                                                                                                                                              • Slide Number 95
                                                                                                                                                              • Slide Number 96
                                                                                                                                                              • Slide Number 97
                                                                                                                                                              • Slide Number 98
                                                                                                                                                              • Slide Number 99
                                                                                                                                                              • DIC Case Studies
                                                                                                                                                              • Case Study 1 - Presentation
                                                                                                                                                              • Case Study 1 ndash Lab Results
                                                                                                                                                              • Case Study 1 ndash Microscopy
                                                                                                                                                              • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                              • Slide Number 105
                                                                                                                                                              • Slide Number 106
                                                                                                                                                              • Slide Number 107
                                                                                                                                                              • Slide Number 108
                                                                                                                                                              • Slide Number 109
                                                                                                                                                              • Slide Number 110
                                                                                                                                                              • Slide Number 111
                                                                                                                                                              • Slide Number 112
                                                                                                                                                              • Slide Number 113
                                                                                                                                                              • Slide Number 114
                                                                                                                                                              • Slide Number 115
                                                                                                                                                              • Slide Number 116
                                                                                                                                                              • Slide Number 117
                                                                                                                                                              • Slide Number 118
                                                                                                                                                              • Slide Number 119
                                                                                                                                                              • Slide Number 120
                                                                                                                                                              • Slide Number 121
                                                                                                                                                              • Slide Number 122
                                                                                                                                                              • Slide Number 123
                                                                                                                                                              • Slide Number 124
                                                                                                                                                              • Slide Number 125
                                                                                                                                                              • DIC Take Home Messages
                                                                                                                                                              • Slide Number 127
                                                                                                                                                              • Slide Number 128

                                                                                                                                                                D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC

                                                                                                                                                                Cut-off value

                                                                                                                                                                Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen

                                                                                                                                                                degradation products Sensitive assay typically with cutoff adapted for DIC

                                                                                                                                                                D-dimer FDPs and DIC

                                                                                                                                                                D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                                                                                                                Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                                                                                                                Follow Up of DIC State of Disease

                                                                                                                                                                Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                                                                                                                Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                                                                                                                FMD-Dimer in DIC Major Differences

                                                                                                                                                                onset of thrombosis

                                                                                                                                                                days

                                                                                                                                                                Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                                                                                                                FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                                                                                                                D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                                                                                                                of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                                                                                                                0

                                                                                                                                                                20

                                                                                                                                                                40

                                                                                                                                                                60

                                                                                                                                                                80

                                                                                                                                                                100

                                                                                                                                                                94 85 90N = 62

                                                                                                                                                                Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                                                                                                                Positivity of Test Results ISTH Score and Disease State

                                                                                                                                                                Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                                                Red bar positive for 2 points of DIC score

                                                                                                                                                                Pink bar positive for 1-2 points of DIC score

                                                                                                                                                                HT hematopoietic tumor

                                                                                                                                                                IF infection

                                                                                                                                                                SC solid cancer

                                                                                                                                                                Markers in Patients with or without DIC

                                                                                                                                                                Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                                                HT hematopoietic tumorIF infectionSC solid cancer

                                                                                                                                                                Comparing an Automated FM vs Manual FSP Test

                                                                                                                                                                Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                                                                                                Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                                                                                                Automated (Mitsubishi) vs Automated (Stago)

                                                                                                                                                                In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                                                                                                Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                                                                                Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                Non Overt DIC Overt DIC

                                                                                                                                                                AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                                                                                Trends in Markers of DIC for Different Patients

                                                                                                                                                                Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                                                                                Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                                                                                Trends in Markers of DIC for Different Patients

                                                                                                                                                                Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                                                                                28 day outcome survival

                                                                                                                                                                28 day outcome death

                                                                                                                                                                Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                                Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                                Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                                                                                Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                                Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                                Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                                                                                DIC Case Studies

                                                                                                                                                                Case Study 1 - Presentation

                                                                                                                                                                18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                                                                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                                                                WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                                                                RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                                                                Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                                                                Hematocrit 195 401 ndash 510

                                                                                                                                                                MCV 95 fL 790 ndash 922 fL

                                                                                                                                                                MPV 12 fL 94 ndash 124 fL

                                                                                                                                                                Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                                                                Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                                                                Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                                                                PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                                                                APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                                                                Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                                                                D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                                                                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                Case Study 1 ndash Microscopy

                                                                                                                                                                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                                                                Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                                                                DIC due to TF release by APL blasts

                                                                                                                                                                Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                                                                Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                                                                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                                                                Case Study 2 ndash Presentation

                                                                                                                                                                TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                                                                PT 30 sec 113 ndash 146 sec

                                                                                                                                                                APTT 75 sec 25 ndash 34 sec

                                                                                                                                                                D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                                                                Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                                                                pH 728 738 to 742

                                                                                                                                                                PaO2 570 mmHg 80-100 mmHg

                                                                                                                                                                WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                                                                ALT 111 IUL 0ndash34 IUL

                                                                                                                                                                AST 61 IUL 0ndash34 IUL

                                                                                                                                                                BUN 303 mgdL 08-13 mgdL

                                                                                                                                                                Case Study 2 ndash Lab Results

                                                                                                                                                                Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                                                                Case Study 2 ndash Diagnosis

                                                                                                                                                                60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                                                                Case Study 3 ndash Presentation

                                                                                                                                                                TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                                                PT 228 sec 113 ndash 146 sec

                                                                                                                                                                APTT 45 sec 25 ndash 34 sec

                                                                                                                                                                D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                                                Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                                                FV Normal 70-120

                                                                                                                                                                FVII Normal 55-170

                                                                                                                                                                FVIII Normal 60-150

                                                                                                                                                                Protein C Normal 70-130

                                                                                                                                                                Hb 134 gdL 14-16 gdL

                                                                                                                                                                WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                                                ALT 32 IUL 0ndash34 IUL

                                                                                                                                                                AST 28 IUL 0ndash34 IUL

                                                                                                                                                                BUN 09 mgdL 08-13 mgdL

                                                                                                                                                                Case Study 3 ndash Lab Results

                                                                                                                                                                Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                                                Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                                                Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                                                Case Study 4 ndash Presentation

                                                                                                                                                                TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                                                PT 28 sec 113 ndash 146 sec

                                                                                                                                                                APTT 71 sec 25 ndash 34 sec

                                                                                                                                                                D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                                                Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                                                FV Normal 70-120

                                                                                                                                                                FVII Normal 55-170

                                                                                                                                                                FVIII Normal 60-150

                                                                                                                                                                Protein C Normal 70-130

                                                                                                                                                                Hb 158 gdL 14-16 gdL

                                                                                                                                                                WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                                                ALT 60 IUL 0ndash34 IUL

                                                                                                                                                                AST 47 IUL 0ndash34 IUL

                                                                                                                                                                BUN 38 mgdL 08-13 mgdL

                                                                                                                                                                Case Study 4 ndash Lab Results

                                                                                                                                                                Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                                                Case Study 4 ndash Diagnosis

                                                                                                                                                                55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                                                Case Study 5 ndash Presentation

                                                                                                                                                                Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                Case Study 5 ndash Lab Results and Time Course

                                                                                                                                                                Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                TEST RESULT REFERENCE RANGE

                                                                                                                                                                Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                                                PT 215 sec 103 ndash 128 sec

                                                                                                                                                                APTT 44 sec 26 ndash 36 sec

                                                                                                                                                                D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                                                Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                                                FII FV FVIII Low Not reported (NR)

                                                                                                                                                                FVII FIX FX vWF Normal NR

                                                                                                                                                                Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                                                DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                                                dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                                                (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                                                (D) Illustration demonstrating repair

                                                                                                                                                                Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                                                Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                                Case Study 6 ndash Presentation

                                                                                                                                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                Case Study 6 ndash Lab Results

                                                                                                                                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                                PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                                INR 658 1 ndash 125

                                                                                                                                                                APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                                D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                                Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                                Albumin 28 gdL NR

                                                                                                                                                                Hb 58 gdL NR

                                                                                                                                                                LDH 1196 UL NR

                                                                                                                                                                SGPT 144 IU NR

                                                                                                                                                                SGOT 88 IU NR

                                                                                                                                                                Bilirubin 32 mgdL NR

                                                                                                                                                                DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                                day postop

                                                                                                                                                                Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                                Case Study 6 ndash Discussion

                                                                                                                                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                                Case Study 7 ndash Presentation

                                                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                                Case Study 7 ndash Presentation

                                                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                Case Study 7 ndash Lab Results vs Time

                                                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                                Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                DIC Take Home Messages

                                                                                                                                                                Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                DIC

                                                                                                                                                                Thank you Questions

                                                                                                                                                                • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                • Learning Objectives
                                                                                                                                                                • Slide Number 3
                                                                                                                                                                • Slide Number 4
                                                                                                                                                                • Slide Number 5
                                                                                                                                                                • Slide Number 6
                                                                                                                                                                • Slide Number 7
                                                                                                                                                                • Slide Number 8
                                                                                                                                                                • Wound Sealing
                                                                                                                                                                • The Three Steps of Hemostasis
                                                                                                                                                                • Vessel Wall
                                                                                                                                                                • Slide Number 12
                                                                                                                                                                • Slide Number 13
                                                                                                                                                                • Platelet Structure UnactivatedActivated
                                                                                                                                                                • Primary Hemostasis
                                                                                                                                                                • Primary Hemostasis Assays
                                                                                                                                                                • Slide Number 17
                                                                                                                                                                • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                • Slide Number 19
                                                                                                                                                                • Coagulation factors
                                                                                                                                                                • Coagulation Assay Mechanisms
                                                                                                                                                                • Slide Number 22
                                                                                                                                                                • Fibrin Formation
                                                                                                                                                                • Slide Number 24
                                                                                                                                                                • Fibrinolysis Overview
                                                                                                                                                                • Fibrinolysis Overview
                                                                                                                                                                • Slide Number 27
                                                                                                                                                                • Fibrinolysis Releases D-dimers
                                                                                                                                                                • Basic Pathophysiology of DIC
                                                                                                                                                                • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                • Clinical Conditions Associated With DIC
                                                                                                                                                                • Frequency of DIC in Selected Disease States
                                                                                                                                                                • Underlying Diseases in DIC Patients
                                                                                                                                                                • Slide Number 36
                                                                                                                                                                • Slide Number 37
                                                                                                                                                                • Slide Number 38
                                                                                                                                                                • Slide Number 39
                                                                                                                                                                • Pathophysiology of DIC
                                                                                                                                                                • Pathogenesis of DIC in Sepsis
                                                                                                                                                                • Host Response in Severe Sepsis
                                                                                                                                                                • Organ Failure in Severe Sepsis
                                                                                                                                                                • Mechanism of DIC in Organ Failure
                                                                                                                                                                • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                • Slide Number 47
                                                                                                                                                                • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                • Mechanism of DIC
                                                                                                                                                                • Pathophysiology of DIC
                                                                                                                                                                • Pathophysiology of DIC - Mechanism
                                                                                                                                                                • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                • Pathophysiology of Overt DIC
                                                                                                                                                                • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                • Slide Number 57
                                                                                                                                                                • Slide Number 58
                                                                                                                                                                • Slide Number 59
                                                                                                                                                                • Slide Number 60
                                                                                                                                                                • Slide Number 61
                                                                                                                                                                • BREAK
                                                                                                                                                                • Diagnostic and Management Approach for DIC
                                                                                                                                                                • Diagnosis of DIC
                                                                                                                                                                • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                • Slide Number 67
                                                                                                                                                                • Slide Number 68
                                                                                                                                                                • British Journal of Haematology Overt DIC Score
                                                                                                                                                                • Slide Number 70
                                                                                                                                                                • Slide Number 71
                                                                                                                                                                • Slide Number 72
                                                                                                                                                                • Slide Number 73
                                                                                                                                                                • DIC Management Goals
                                                                                                                                                                • DIC Management and Treatment
                                                                                                                                                                • DIC Management Strategies
                                                                                                                                                                • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                • D-dimer FDPs and DIC
                                                                                                                                                                • D-Dimer and FDPs in DIC
                                                                                                                                                                • Follow Up of DIC State of Disease
                                                                                                                                                                • FMD-Dimer in DIC Major Differences
                                                                                                                                                                • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                • Slide Number 85
                                                                                                                                                                • Slide Number 86
                                                                                                                                                                • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                • Slide Number 94
                                                                                                                                                                • Slide Number 95
                                                                                                                                                                • Slide Number 96
                                                                                                                                                                • Slide Number 97
                                                                                                                                                                • Slide Number 98
                                                                                                                                                                • Slide Number 99
                                                                                                                                                                • DIC Case Studies
                                                                                                                                                                • Case Study 1 - Presentation
                                                                                                                                                                • Case Study 1 ndash Lab Results
                                                                                                                                                                • Case Study 1 ndash Microscopy
                                                                                                                                                                • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                • Slide Number 105
                                                                                                                                                                • Slide Number 106
                                                                                                                                                                • Slide Number 107
                                                                                                                                                                • Slide Number 108
                                                                                                                                                                • Slide Number 109
                                                                                                                                                                • Slide Number 110
                                                                                                                                                                • Slide Number 111
                                                                                                                                                                • Slide Number 112
                                                                                                                                                                • Slide Number 113
                                                                                                                                                                • Slide Number 114
                                                                                                                                                                • Slide Number 115
                                                                                                                                                                • Slide Number 116
                                                                                                                                                                • Slide Number 117
                                                                                                                                                                • Slide Number 118
                                                                                                                                                                • Slide Number 119
                                                                                                                                                                • Slide Number 120
                                                                                                                                                                • Slide Number 121
                                                                                                                                                                • Slide Number 122
                                                                                                                                                                • Slide Number 123
                                                                                                                                                                • Slide Number 124
                                                                                                                                                                • Slide Number 125
                                                                                                                                                                • DIC Take Home Messages
                                                                                                                                                                • Slide Number 127
                                                                                                                                                                • Slide Number 128

                                                                                                                                                                  D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC

                                                                                                                                                                  Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80

                                                                                                                                                                  Follow Up of DIC State of Disease

                                                                                                                                                                  Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                                                                                                                  Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                                                                                                                  FMD-Dimer in DIC Major Differences

                                                                                                                                                                  onset of thrombosis

                                                                                                                                                                  days

                                                                                                                                                                  Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                                                                                                                  FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                                                                                                                  D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                                                                                                                  of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                                                                                                                  0

                                                                                                                                                                  20

                                                                                                                                                                  40

                                                                                                                                                                  60

                                                                                                                                                                  80

                                                                                                                                                                  100

                                                                                                                                                                  94 85 90N = 62

                                                                                                                                                                  Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                                                                                                                  Positivity of Test Results ISTH Score and Disease State

                                                                                                                                                                  Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                                                  Red bar positive for 2 points of DIC score

                                                                                                                                                                  Pink bar positive for 1-2 points of DIC score

                                                                                                                                                                  HT hematopoietic tumor

                                                                                                                                                                  IF infection

                                                                                                                                                                  SC solid cancer

                                                                                                                                                                  Markers in Patients with or without DIC

                                                                                                                                                                  Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                                                  HT hematopoietic tumorIF infectionSC solid cancer

                                                                                                                                                                  Comparing an Automated FM vs Manual FSP Test

                                                                                                                                                                  Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                                                                                                  Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                                                                                                  Automated (Mitsubishi) vs Automated (Stago)

                                                                                                                                                                  In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                                                                                                  Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                  In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                  In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                  In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                  Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                  No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                                                                                  Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                  Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                  Non Overt DIC Overt DIC

                                                                                                                                                                  AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                                                                                  Trends in Markers of DIC for Different Patients

                                                                                                                                                                  Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                                                                                  Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                                                                                  Trends in Markers of DIC for Different Patients

                                                                                                                                                                  Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                  FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                                                                                  28 day outcome survival

                                                                                                                                                                  28 day outcome death

                                                                                                                                                                  Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                                  Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                                  Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                                                                                  Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                                  Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                                  Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                                                                                  DIC Case Studies

                                                                                                                                                                  Case Study 1 - Presentation

                                                                                                                                                                  18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                                                                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                  Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                                                                  WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                                                                  RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                                                                  Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                                                                  Hematocrit 195 401 ndash 510

                                                                                                                                                                  MCV 95 fL 790 ndash 922 fL

                                                                                                                                                                  MPV 12 fL 94 ndash 124 fL

                                                                                                                                                                  Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                                                                  Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                                                                  Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                                                                  PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                                                                  APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                                                                  Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                                                                  D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                                                                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                  Case Study 1 ndash Microscopy

                                                                                                                                                                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                  Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                                                                  Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                                                                  DIC due to TF release by APL blasts

                                                                                                                                                                  Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                                                                  Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                                                                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                  20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                                                                  Case Study 2 ndash Presentation

                                                                                                                                                                  TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                                                                  PT 30 sec 113 ndash 146 sec

                                                                                                                                                                  APTT 75 sec 25 ndash 34 sec

                                                                                                                                                                  D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                                                                  Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                                                                  pH 728 738 to 742

                                                                                                                                                                  PaO2 570 mmHg 80-100 mmHg

                                                                                                                                                                  WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                                                                  ALT 111 IUL 0ndash34 IUL

                                                                                                                                                                  AST 61 IUL 0ndash34 IUL

                                                                                                                                                                  BUN 303 mgdL 08-13 mgdL

                                                                                                                                                                  Case Study 2 ndash Lab Results

                                                                                                                                                                  Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                                                                  Case Study 2 ndash Diagnosis

                                                                                                                                                                  60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                                                                  Case Study 3 ndash Presentation

                                                                                                                                                                  TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                                                  PT 228 sec 113 ndash 146 sec

                                                                                                                                                                  APTT 45 sec 25 ndash 34 sec

                                                                                                                                                                  D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                                                  Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                                                  FV Normal 70-120

                                                                                                                                                                  FVII Normal 55-170

                                                                                                                                                                  FVIII Normal 60-150

                                                                                                                                                                  Protein C Normal 70-130

                                                                                                                                                                  Hb 134 gdL 14-16 gdL

                                                                                                                                                                  WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                                                  ALT 32 IUL 0ndash34 IUL

                                                                                                                                                                  AST 28 IUL 0ndash34 IUL

                                                                                                                                                                  BUN 09 mgdL 08-13 mgdL

                                                                                                                                                                  Case Study 3 ndash Lab Results

                                                                                                                                                                  Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                                                  Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                                                  Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                                                  Case Study 4 ndash Presentation

                                                                                                                                                                  TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                                                  PT 28 sec 113 ndash 146 sec

                                                                                                                                                                  APTT 71 sec 25 ndash 34 sec

                                                                                                                                                                  D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                                                  Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                                                  FV Normal 70-120

                                                                                                                                                                  FVII Normal 55-170

                                                                                                                                                                  FVIII Normal 60-150

                                                                                                                                                                  Protein C Normal 70-130

                                                                                                                                                                  Hb 158 gdL 14-16 gdL

                                                                                                                                                                  WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                                                  ALT 60 IUL 0ndash34 IUL

                                                                                                                                                                  AST 47 IUL 0ndash34 IUL

                                                                                                                                                                  BUN 38 mgdL 08-13 mgdL

                                                                                                                                                                  Case Study 4 ndash Lab Results

                                                                                                                                                                  Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                                                  Case Study 4 ndash Diagnosis

                                                                                                                                                                  55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                                                  Case Study 5 ndash Presentation

                                                                                                                                                                  Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                  Case Study 5 ndash Lab Results and Time Course

                                                                                                                                                                  Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                  TEST RESULT REFERENCE RANGE

                                                                                                                                                                  Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                                                  PT 215 sec 103 ndash 128 sec

                                                                                                                                                                  APTT 44 sec 26 ndash 36 sec

                                                                                                                                                                  D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                                                  Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                                                  FII FV FVIII Low Not reported (NR)

                                                                                                                                                                  FVII FIX FX vWF Normal NR

                                                                                                                                                                  Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                                                  DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                                                  dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                                                  (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                                                  (D) Illustration demonstrating repair

                                                                                                                                                                  Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                                                  Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                  29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                                  Case Study 6 ndash Presentation

                                                                                                                                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                  Case Study 6 ndash Lab Results

                                                                                                                                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                  TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                                  PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                                  INR 658 1 ndash 125

                                                                                                                                                                  APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                                  D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                                  Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                                  Albumin 28 gdL NR

                                                                                                                                                                  Hb 58 gdL NR

                                                                                                                                                                  LDH 1196 UL NR

                                                                                                                                                                  SGPT 144 IU NR

                                                                                                                                                                  SGOT 88 IU NR

                                                                                                                                                                  Bilirubin 32 mgdL NR

                                                                                                                                                                  DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                                  day postop

                                                                                                                                                                  Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                  HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                                  Case Study 6 ndash Discussion

                                                                                                                                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                  44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                                  Case Study 7 ndash Presentation

                                                                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                  On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                                  Case Study 7 ndash Presentation

                                                                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                  Case Study 7 ndash Lab Results vs Time

                                                                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                  Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                                  Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                  On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                  Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                  DIC Take Home Messages

                                                                                                                                                                  Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                  Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                  DIC

                                                                                                                                                                  Thank you Questions

                                                                                                                                                                  • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                  • Learning Objectives
                                                                                                                                                                  • Slide Number 3
                                                                                                                                                                  • Slide Number 4
                                                                                                                                                                  • Slide Number 5
                                                                                                                                                                  • Slide Number 6
                                                                                                                                                                  • Slide Number 7
                                                                                                                                                                  • Slide Number 8
                                                                                                                                                                  • Wound Sealing
                                                                                                                                                                  • The Three Steps of Hemostasis
                                                                                                                                                                  • Vessel Wall
                                                                                                                                                                  • Slide Number 12
                                                                                                                                                                  • Slide Number 13
                                                                                                                                                                  • Platelet Structure UnactivatedActivated
                                                                                                                                                                  • Primary Hemostasis
                                                                                                                                                                  • Primary Hemostasis Assays
                                                                                                                                                                  • Slide Number 17
                                                                                                                                                                  • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                  • Slide Number 19
                                                                                                                                                                  • Coagulation factors
                                                                                                                                                                  • Coagulation Assay Mechanisms
                                                                                                                                                                  • Slide Number 22
                                                                                                                                                                  • Fibrin Formation
                                                                                                                                                                  • Slide Number 24
                                                                                                                                                                  • Fibrinolysis Overview
                                                                                                                                                                  • Fibrinolysis Overview
                                                                                                                                                                  • Slide Number 27
                                                                                                                                                                  • Fibrinolysis Releases D-dimers
                                                                                                                                                                  • Basic Pathophysiology of DIC
                                                                                                                                                                  • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                  • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                  • Clinical Conditions Associated With DIC
                                                                                                                                                                  • Frequency of DIC in Selected Disease States
                                                                                                                                                                  • Underlying Diseases in DIC Patients
                                                                                                                                                                  • Slide Number 36
                                                                                                                                                                  • Slide Number 37
                                                                                                                                                                  • Slide Number 38
                                                                                                                                                                  • Slide Number 39
                                                                                                                                                                  • Pathophysiology of DIC
                                                                                                                                                                  • Pathogenesis of DIC in Sepsis
                                                                                                                                                                  • Host Response in Severe Sepsis
                                                                                                                                                                  • Organ Failure in Severe Sepsis
                                                                                                                                                                  • Mechanism of DIC in Organ Failure
                                                                                                                                                                  • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                  • Slide Number 47
                                                                                                                                                                  • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                  • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                  • Mechanism of DIC
                                                                                                                                                                  • Pathophysiology of DIC
                                                                                                                                                                  • Pathophysiology of DIC - Mechanism
                                                                                                                                                                  • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                  • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                  • Pathophysiology of Overt DIC
                                                                                                                                                                  • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                  • Slide Number 57
                                                                                                                                                                  • Slide Number 58
                                                                                                                                                                  • Slide Number 59
                                                                                                                                                                  • Slide Number 60
                                                                                                                                                                  • Slide Number 61
                                                                                                                                                                  • BREAK
                                                                                                                                                                  • Diagnostic and Management Approach for DIC
                                                                                                                                                                  • Diagnosis of DIC
                                                                                                                                                                  • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                  • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                  • Slide Number 67
                                                                                                                                                                  • Slide Number 68
                                                                                                                                                                  • British Journal of Haematology Overt DIC Score
                                                                                                                                                                  • Slide Number 70
                                                                                                                                                                  • Slide Number 71
                                                                                                                                                                  • Slide Number 72
                                                                                                                                                                  • Slide Number 73
                                                                                                                                                                  • DIC Management Goals
                                                                                                                                                                  • DIC Management and Treatment
                                                                                                                                                                  • DIC Management Strategies
                                                                                                                                                                  • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                  • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                  • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                  • D-dimer FDPs and DIC
                                                                                                                                                                  • D-Dimer and FDPs in DIC
                                                                                                                                                                  • Follow Up of DIC State of Disease
                                                                                                                                                                  • FMD-Dimer in DIC Major Differences
                                                                                                                                                                  • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                  • Slide Number 85
                                                                                                                                                                  • Slide Number 86
                                                                                                                                                                  • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                  • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                  • Slide Number 94
                                                                                                                                                                  • Slide Number 95
                                                                                                                                                                  • Slide Number 96
                                                                                                                                                                  • Slide Number 97
                                                                                                                                                                  • Slide Number 98
                                                                                                                                                                  • Slide Number 99
                                                                                                                                                                  • DIC Case Studies
                                                                                                                                                                  • Case Study 1 - Presentation
                                                                                                                                                                  • Case Study 1 ndash Lab Results
                                                                                                                                                                  • Case Study 1 ndash Microscopy
                                                                                                                                                                  • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                  • Slide Number 105
                                                                                                                                                                  • Slide Number 106
                                                                                                                                                                  • Slide Number 107
                                                                                                                                                                  • Slide Number 108
                                                                                                                                                                  • Slide Number 109
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                                                                                                                                                                  • Slide Number 111
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                                                                                                                                                                  • Slide Number 115
                                                                                                                                                                  • Slide Number 116
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                                                                                                                                                                  • Slide Number 122
                                                                                                                                                                  • Slide Number 123
                                                                                                                                                                  • Slide Number 124
                                                                                                                                                                  • Slide Number 125
                                                                                                                                                                  • DIC Take Home Messages
                                                                                                                                                                  • Slide Number 127
                                                                                                                                                                  • Slide Number 128

                                                                                                                                                                    Follow Up of DIC State of Disease

                                                                                                                                                                    Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8

                                                                                                                                                                    Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility

                                                                                                                                                                    FMD-Dimer in DIC Major Differences

                                                                                                                                                                    onset of thrombosis

                                                                                                                                                                    days

                                                                                                                                                                    Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                                                                                                                    FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                                                                                                                    D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                                                                                                                    of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                                                                                                                    0

                                                                                                                                                                    20

                                                                                                                                                                    40

                                                                                                                                                                    60

                                                                                                                                                                    80

                                                                                                                                                                    100

                                                                                                                                                                    94 85 90N = 62

                                                                                                                                                                    Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                                                                                                                    Positivity of Test Results ISTH Score and Disease State

                                                                                                                                                                    Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                                                    Red bar positive for 2 points of DIC score

                                                                                                                                                                    Pink bar positive for 1-2 points of DIC score

                                                                                                                                                                    HT hematopoietic tumor

                                                                                                                                                                    IF infection

                                                                                                                                                                    SC solid cancer

                                                                                                                                                                    Markers in Patients with or without DIC

                                                                                                                                                                    Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                                                    HT hematopoietic tumorIF infectionSC solid cancer

                                                                                                                                                                    Comparing an Automated FM vs Manual FSP Test

                                                                                                                                                                    Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                                                                                                    Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                                                                                                    Automated (Mitsubishi) vs Automated (Stago)

                                                                                                                                                                    In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                                                                                                    Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                    In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                    In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                    In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                    Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                    No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                                                                                    Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                    Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                    Non Overt DIC Overt DIC

                                                                                                                                                                    AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                                                                                    Trends in Markers of DIC for Different Patients

                                                                                                                                                                    Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                                                                                    Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                                                                                    Trends in Markers of DIC for Different Patients

                                                                                                                                                                    Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                    FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                                                                                    28 day outcome survival

                                                                                                                                                                    28 day outcome death

                                                                                                                                                                    Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                                    Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                                    Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                                                                                    Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                                    Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                                    Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                                                                                    DIC Case Studies

                                                                                                                                                                    Case Study 1 - Presentation

                                                                                                                                                                    18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                                                                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                    Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                                                                    WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                                                                    RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                                                                    Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                                                                    Hematocrit 195 401 ndash 510

                                                                                                                                                                    MCV 95 fL 790 ndash 922 fL

                                                                                                                                                                    MPV 12 fL 94 ndash 124 fL

                                                                                                                                                                    Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                                                                    Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                                                                    Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                                                                    PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                                                                    APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                                                                    Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                                                                    D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                                                                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                    Case Study 1 ndash Microscopy

                                                                                                                                                                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                    Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                                                                    Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                                                                    DIC due to TF release by APL blasts

                                                                                                                                                                    Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                                                                    Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                                                                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                    20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                                                                    Case Study 2 ndash Presentation

                                                                                                                                                                    TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                                                                    PT 30 sec 113 ndash 146 sec

                                                                                                                                                                    APTT 75 sec 25 ndash 34 sec

                                                                                                                                                                    D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                                                                    Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                                                                    pH 728 738 to 742

                                                                                                                                                                    PaO2 570 mmHg 80-100 mmHg

                                                                                                                                                                    WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                                                                    ALT 111 IUL 0ndash34 IUL

                                                                                                                                                                    AST 61 IUL 0ndash34 IUL

                                                                                                                                                                    BUN 303 mgdL 08-13 mgdL

                                                                                                                                                                    Case Study 2 ndash Lab Results

                                                                                                                                                                    Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                                                                    Case Study 2 ndash Diagnosis

                                                                                                                                                                    60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                                                                    Case Study 3 ndash Presentation

                                                                                                                                                                    TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                                                    PT 228 sec 113 ndash 146 sec

                                                                                                                                                                    APTT 45 sec 25 ndash 34 sec

                                                                                                                                                                    D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                                                    Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                                                    FV Normal 70-120

                                                                                                                                                                    FVII Normal 55-170

                                                                                                                                                                    FVIII Normal 60-150

                                                                                                                                                                    Protein C Normal 70-130

                                                                                                                                                                    Hb 134 gdL 14-16 gdL

                                                                                                                                                                    WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                                                    ALT 32 IUL 0ndash34 IUL

                                                                                                                                                                    AST 28 IUL 0ndash34 IUL

                                                                                                                                                                    BUN 09 mgdL 08-13 mgdL

                                                                                                                                                                    Case Study 3 ndash Lab Results

                                                                                                                                                                    Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                                                    Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                                                    Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                                                    Case Study 4 ndash Presentation

                                                                                                                                                                    TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                                                    PT 28 sec 113 ndash 146 sec

                                                                                                                                                                    APTT 71 sec 25 ndash 34 sec

                                                                                                                                                                    D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                                                    Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                                                    FV Normal 70-120

                                                                                                                                                                    FVII Normal 55-170

                                                                                                                                                                    FVIII Normal 60-150

                                                                                                                                                                    Protein C Normal 70-130

                                                                                                                                                                    Hb 158 gdL 14-16 gdL

                                                                                                                                                                    WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                                                    ALT 60 IUL 0ndash34 IUL

                                                                                                                                                                    AST 47 IUL 0ndash34 IUL

                                                                                                                                                                    BUN 38 mgdL 08-13 mgdL

                                                                                                                                                                    Case Study 4 ndash Lab Results

                                                                                                                                                                    Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                                                    Case Study 4 ndash Diagnosis

                                                                                                                                                                    55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                                                    Case Study 5 ndash Presentation

                                                                                                                                                                    Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                    Case Study 5 ndash Lab Results and Time Course

                                                                                                                                                                    Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                    TEST RESULT REFERENCE RANGE

                                                                                                                                                                    Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                                                    PT 215 sec 103 ndash 128 sec

                                                                                                                                                                    APTT 44 sec 26 ndash 36 sec

                                                                                                                                                                    D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                                                    Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                                                    FII FV FVIII Low Not reported (NR)

                                                                                                                                                                    FVII FIX FX vWF Normal NR

                                                                                                                                                                    Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                                                    DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                                                    dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                                                    (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                                                    (D) Illustration demonstrating repair

                                                                                                                                                                    Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                                                    Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                    29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                                    Case Study 6 ndash Presentation

                                                                                                                                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                    Case Study 6 ndash Lab Results

                                                                                                                                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                    TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                                    PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                                    INR 658 1 ndash 125

                                                                                                                                                                    APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                                    D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                                    Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                                    Albumin 28 gdL NR

                                                                                                                                                                    Hb 58 gdL NR

                                                                                                                                                                    LDH 1196 UL NR

                                                                                                                                                                    SGPT 144 IU NR

                                                                                                                                                                    SGOT 88 IU NR

                                                                                                                                                                    Bilirubin 32 mgdL NR

                                                                                                                                                                    DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                                    day postop

                                                                                                                                                                    Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                    HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                                    Case Study 6 ndash Discussion

                                                                                                                                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                    44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                                    Case Study 7 ndash Presentation

                                                                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                    On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                                    Case Study 7 ndash Presentation

                                                                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                    Case Study 7 ndash Lab Results vs Time

                                                                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                    Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                                    Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                    On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                    Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                    DIC Take Home Messages

                                                                                                                                                                    Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                    Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                    DIC

                                                                                                                                                                    Thank you Questions

                                                                                                                                                                    • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                    • Learning Objectives
                                                                                                                                                                    • Slide Number 3
                                                                                                                                                                    • Slide Number 4
                                                                                                                                                                    • Slide Number 5
                                                                                                                                                                    • Slide Number 6
                                                                                                                                                                    • Slide Number 7
                                                                                                                                                                    • Slide Number 8
                                                                                                                                                                    • Wound Sealing
                                                                                                                                                                    • The Three Steps of Hemostasis
                                                                                                                                                                    • Vessel Wall
                                                                                                                                                                    • Slide Number 12
                                                                                                                                                                    • Slide Number 13
                                                                                                                                                                    • Platelet Structure UnactivatedActivated
                                                                                                                                                                    • Primary Hemostasis
                                                                                                                                                                    • Primary Hemostasis Assays
                                                                                                                                                                    • Slide Number 17
                                                                                                                                                                    • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                    • Slide Number 19
                                                                                                                                                                    • Coagulation factors
                                                                                                                                                                    • Coagulation Assay Mechanisms
                                                                                                                                                                    • Slide Number 22
                                                                                                                                                                    • Fibrin Formation
                                                                                                                                                                    • Slide Number 24
                                                                                                                                                                    • Fibrinolysis Overview
                                                                                                                                                                    • Fibrinolysis Overview
                                                                                                                                                                    • Slide Number 27
                                                                                                                                                                    • Fibrinolysis Releases D-dimers
                                                                                                                                                                    • Basic Pathophysiology of DIC
                                                                                                                                                                    • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                    • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                    • Clinical Conditions Associated With DIC
                                                                                                                                                                    • Frequency of DIC in Selected Disease States
                                                                                                                                                                    • Underlying Diseases in DIC Patients
                                                                                                                                                                    • Slide Number 36
                                                                                                                                                                    • Slide Number 37
                                                                                                                                                                    • Slide Number 38
                                                                                                                                                                    • Slide Number 39
                                                                                                                                                                    • Pathophysiology of DIC
                                                                                                                                                                    • Pathogenesis of DIC in Sepsis
                                                                                                                                                                    • Host Response in Severe Sepsis
                                                                                                                                                                    • Organ Failure in Severe Sepsis
                                                                                                                                                                    • Mechanism of DIC in Organ Failure
                                                                                                                                                                    • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                    • Slide Number 47
                                                                                                                                                                    • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                    • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                    • Mechanism of DIC
                                                                                                                                                                    • Pathophysiology of DIC
                                                                                                                                                                    • Pathophysiology of DIC - Mechanism
                                                                                                                                                                    • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                    • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                    • Pathophysiology of Overt DIC
                                                                                                                                                                    • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                    • Slide Number 57
                                                                                                                                                                    • Slide Number 58
                                                                                                                                                                    • Slide Number 59
                                                                                                                                                                    • Slide Number 60
                                                                                                                                                                    • Slide Number 61
                                                                                                                                                                    • BREAK
                                                                                                                                                                    • Diagnostic and Management Approach for DIC
                                                                                                                                                                    • Diagnosis of DIC
                                                                                                                                                                    • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                    • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                    • Slide Number 67
                                                                                                                                                                    • Slide Number 68
                                                                                                                                                                    • British Journal of Haematology Overt DIC Score
                                                                                                                                                                    • Slide Number 70
                                                                                                                                                                    • Slide Number 71
                                                                                                                                                                    • Slide Number 72
                                                                                                                                                                    • Slide Number 73
                                                                                                                                                                    • DIC Management Goals
                                                                                                                                                                    • DIC Management and Treatment
                                                                                                                                                                    • DIC Management Strategies
                                                                                                                                                                    • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                    • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                    • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                    • D-dimer FDPs and DIC
                                                                                                                                                                    • D-Dimer and FDPs in DIC
                                                                                                                                                                    • Follow Up of DIC State of Disease
                                                                                                                                                                    • FMD-Dimer in DIC Major Differences
                                                                                                                                                                    • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                    • Slide Number 85
                                                                                                                                                                    • Slide Number 86
                                                                                                                                                                    • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                    • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                    • Slide Number 94
                                                                                                                                                                    • Slide Number 95
                                                                                                                                                                    • Slide Number 96
                                                                                                                                                                    • Slide Number 97
                                                                                                                                                                    • Slide Number 98
                                                                                                                                                                    • Slide Number 99
                                                                                                                                                                    • DIC Case Studies
                                                                                                                                                                    • Case Study 1 - Presentation
                                                                                                                                                                    • Case Study 1 ndash Lab Results
                                                                                                                                                                    • Case Study 1 ndash Microscopy
                                                                                                                                                                    • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                    • Slide Number 105
                                                                                                                                                                    • Slide Number 106
                                                                                                                                                                    • Slide Number 107
                                                                                                                                                                    • Slide Number 108
                                                                                                                                                                    • Slide Number 109
                                                                                                                                                                    • Slide Number 110
                                                                                                                                                                    • Slide Number 111
                                                                                                                                                                    • Slide Number 112
                                                                                                                                                                    • Slide Number 113
                                                                                                                                                                    • Slide Number 114
                                                                                                                                                                    • Slide Number 115
                                                                                                                                                                    • Slide Number 116
                                                                                                                                                                    • Slide Number 117
                                                                                                                                                                    • Slide Number 118
                                                                                                                                                                    • Slide Number 119
                                                                                                                                                                    • Slide Number 120
                                                                                                                                                                    • Slide Number 121
                                                                                                                                                                    • Slide Number 122
                                                                                                                                                                    • Slide Number 123
                                                                                                                                                                    • Slide Number 124
                                                                                                                                                                    • Slide Number 125
                                                                                                                                                                    • DIC Take Home Messages
                                                                                                                                                                    • Slide Number 127
                                                                                                                                                                    • Slide Number 128

                                                                                                                                                                      FMD-Dimer in DIC Major Differences

                                                                                                                                                                      onset of thrombosis

                                                                                                                                                                      days

                                                                                                                                                                      Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8

                                                                                                                                                                      FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)

                                                                                                                                                                      D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)

                                                                                                                                                                      of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                                                                                                                      0

                                                                                                                                                                      20

                                                                                                                                                                      40

                                                                                                                                                                      60

                                                                                                                                                                      80

                                                                                                                                                                      100

                                                                                                                                                                      94 85 90N = 62

                                                                                                                                                                      Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                                                                                                                      Positivity of Test Results ISTH Score and Disease State

                                                                                                                                                                      Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                                                      Red bar positive for 2 points of DIC score

                                                                                                                                                                      Pink bar positive for 1-2 points of DIC score

                                                                                                                                                                      HT hematopoietic tumor

                                                                                                                                                                      IF infection

                                                                                                                                                                      SC solid cancer

                                                                                                                                                                      Markers in Patients with or without DIC

                                                                                                                                                                      Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                                                      HT hematopoietic tumorIF infectionSC solid cancer

                                                                                                                                                                      Comparing an Automated FM vs Manual FSP Test

                                                                                                                                                                      Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                                                                                                      Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                                                                                                      Automated (Mitsubishi) vs Automated (Stago)

                                                                                                                                                                      In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                                                                                                      Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                      In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                      In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                      In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                      Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                      No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                                                                                      Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                      Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                      Non Overt DIC Overt DIC

                                                                                                                                                                      AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                                                                                      Trends in Markers of DIC for Different Patients

                                                                                                                                                                      Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                                                                                      Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                                                                                      Trends in Markers of DIC for Different Patients

                                                                                                                                                                      Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                      FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                                                                                      28 day outcome survival

                                                                                                                                                                      28 day outcome death

                                                                                                                                                                      Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                                      Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                                      Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                                                                                      Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                                      Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                                      Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                                                                                      DIC Case Studies

                                                                                                                                                                      Case Study 1 - Presentation

                                                                                                                                                                      18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                                                                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                      Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                                                                      WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                                                                      RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                                                                      Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                                                                      Hematocrit 195 401 ndash 510

                                                                                                                                                                      MCV 95 fL 790 ndash 922 fL

                                                                                                                                                                      MPV 12 fL 94 ndash 124 fL

                                                                                                                                                                      Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                                                                      Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                                                                      Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                                                                      PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                                                                      APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                                                                      Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                                                                      D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                                                                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                      Case Study 1 ndash Microscopy

                                                                                                                                                                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                      Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                                                                      Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                                                                      DIC due to TF release by APL blasts

                                                                                                                                                                      Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                                                                      Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                                                                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                      20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                                                                      Case Study 2 ndash Presentation

                                                                                                                                                                      TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                                                                      PT 30 sec 113 ndash 146 sec

                                                                                                                                                                      APTT 75 sec 25 ndash 34 sec

                                                                                                                                                                      D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                                                                      Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                                                                      pH 728 738 to 742

                                                                                                                                                                      PaO2 570 mmHg 80-100 mmHg

                                                                                                                                                                      WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                                                                      ALT 111 IUL 0ndash34 IUL

                                                                                                                                                                      AST 61 IUL 0ndash34 IUL

                                                                                                                                                                      BUN 303 mgdL 08-13 mgdL

                                                                                                                                                                      Case Study 2 ndash Lab Results

                                                                                                                                                                      Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                                                                      Case Study 2 ndash Diagnosis

                                                                                                                                                                      60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                                                                      Case Study 3 ndash Presentation

                                                                                                                                                                      TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                                                      PT 228 sec 113 ndash 146 sec

                                                                                                                                                                      APTT 45 sec 25 ndash 34 sec

                                                                                                                                                                      D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                                                      Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                                                      FV Normal 70-120

                                                                                                                                                                      FVII Normal 55-170

                                                                                                                                                                      FVIII Normal 60-150

                                                                                                                                                                      Protein C Normal 70-130

                                                                                                                                                                      Hb 134 gdL 14-16 gdL

                                                                                                                                                                      WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                                                      ALT 32 IUL 0ndash34 IUL

                                                                                                                                                                      AST 28 IUL 0ndash34 IUL

                                                                                                                                                                      BUN 09 mgdL 08-13 mgdL

                                                                                                                                                                      Case Study 3 ndash Lab Results

                                                                                                                                                                      Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                                                      Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                                                      Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                                                      Case Study 4 ndash Presentation

                                                                                                                                                                      TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                                                      PT 28 sec 113 ndash 146 sec

                                                                                                                                                                      APTT 71 sec 25 ndash 34 sec

                                                                                                                                                                      D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                                                      Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                                                      FV Normal 70-120

                                                                                                                                                                      FVII Normal 55-170

                                                                                                                                                                      FVIII Normal 60-150

                                                                                                                                                                      Protein C Normal 70-130

                                                                                                                                                                      Hb 158 gdL 14-16 gdL

                                                                                                                                                                      WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                                                      ALT 60 IUL 0ndash34 IUL

                                                                                                                                                                      AST 47 IUL 0ndash34 IUL

                                                                                                                                                                      BUN 38 mgdL 08-13 mgdL

                                                                                                                                                                      Case Study 4 ndash Lab Results

                                                                                                                                                                      Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                                                      Case Study 4 ndash Diagnosis

                                                                                                                                                                      55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                                                      Case Study 5 ndash Presentation

                                                                                                                                                                      Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                      Case Study 5 ndash Lab Results and Time Course

                                                                                                                                                                      Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                      TEST RESULT REFERENCE RANGE

                                                                                                                                                                      Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                                                      PT 215 sec 103 ndash 128 sec

                                                                                                                                                                      APTT 44 sec 26 ndash 36 sec

                                                                                                                                                                      D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                                                      Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                                                      FII FV FVIII Low Not reported (NR)

                                                                                                                                                                      FVII FIX FX vWF Normal NR

                                                                                                                                                                      Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                                                      DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                                                      dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                                                      (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                                                      (D) Illustration demonstrating repair

                                                                                                                                                                      Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                                                      Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                      29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                                      Case Study 6 ndash Presentation

                                                                                                                                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                      Case Study 6 ndash Lab Results

                                                                                                                                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                      TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                                      PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                                      INR 658 1 ndash 125

                                                                                                                                                                      APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                                      D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                                      Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                                      Albumin 28 gdL NR

                                                                                                                                                                      Hb 58 gdL NR

                                                                                                                                                                      LDH 1196 UL NR

                                                                                                                                                                      SGPT 144 IU NR

                                                                                                                                                                      SGOT 88 IU NR

                                                                                                                                                                      Bilirubin 32 mgdL NR

                                                                                                                                                                      DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                                      day postop

                                                                                                                                                                      Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                      HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                                      Case Study 6 ndash Discussion

                                                                                                                                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                      44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                                      Case Study 7 ndash Presentation

                                                                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                      On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                                      Case Study 7 ndash Presentation

                                                                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                      Case Study 7 ndash Lab Results vs Time

                                                                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                      Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                                      Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                      On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                      Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                      DIC Take Home Messages

                                                                                                                                                                      Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                      Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                      DIC

                                                                                                                                                                      Thank you Questions

                                                                                                                                                                      • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                      • Learning Objectives
                                                                                                                                                                      • Slide Number 3
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                                                                                                                                                                      • Slide Number 6
                                                                                                                                                                      • Slide Number 7
                                                                                                                                                                      • Slide Number 8
                                                                                                                                                                      • Wound Sealing
                                                                                                                                                                      • The Three Steps of Hemostasis
                                                                                                                                                                      • Vessel Wall
                                                                                                                                                                      • Slide Number 12
                                                                                                                                                                      • Slide Number 13
                                                                                                                                                                      • Platelet Structure UnactivatedActivated
                                                                                                                                                                      • Primary Hemostasis
                                                                                                                                                                      • Primary Hemostasis Assays
                                                                                                                                                                      • Slide Number 17
                                                                                                                                                                      • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                      • Slide Number 19
                                                                                                                                                                      • Coagulation factors
                                                                                                                                                                      • Coagulation Assay Mechanisms
                                                                                                                                                                      • Slide Number 22
                                                                                                                                                                      • Fibrin Formation
                                                                                                                                                                      • Slide Number 24
                                                                                                                                                                      • Fibrinolysis Overview
                                                                                                                                                                      • Fibrinolysis Overview
                                                                                                                                                                      • Slide Number 27
                                                                                                                                                                      • Fibrinolysis Releases D-dimers
                                                                                                                                                                      • Basic Pathophysiology of DIC
                                                                                                                                                                      • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                      • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                      • Clinical Conditions Associated With DIC
                                                                                                                                                                      • Frequency of DIC in Selected Disease States
                                                                                                                                                                      • Underlying Diseases in DIC Patients
                                                                                                                                                                      • Slide Number 36
                                                                                                                                                                      • Slide Number 37
                                                                                                                                                                      • Slide Number 38
                                                                                                                                                                      • Slide Number 39
                                                                                                                                                                      • Pathophysiology of DIC
                                                                                                                                                                      • Pathogenesis of DIC in Sepsis
                                                                                                                                                                      • Host Response in Severe Sepsis
                                                                                                                                                                      • Organ Failure in Severe Sepsis
                                                                                                                                                                      • Mechanism of DIC in Organ Failure
                                                                                                                                                                      • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                      • Slide Number 47
                                                                                                                                                                      • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                      • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                      • Mechanism of DIC
                                                                                                                                                                      • Pathophysiology of DIC
                                                                                                                                                                      • Pathophysiology of DIC - Mechanism
                                                                                                                                                                      • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                      • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                      • Pathophysiology of Overt DIC
                                                                                                                                                                      • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                      • Slide Number 57
                                                                                                                                                                      • Slide Number 58
                                                                                                                                                                      • Slide Number 59
                                                                                                                                                                      • Slide Number 60
                                                                                                                                                                      • Slide Number 61
                                                                                                                                                                      • BREAK
                                                                                                                                                                      • Diagnostic and Management Approach for DIC
                                                                                                                                                                      • Diagnosis of DIC
                                                                                                                                                                      • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                      • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                      • Slide Number 67
                                                                                                                                                                      • Slide Number 68
                                                                                                                                                                      • British Journal of Haematology Overt DIC Score
                                                                                                                                                                      • Slide Number 70
                                                                                                                                                                      • Slide Number 71
                                                                                                                                                                      • Slide Number 72
                                                                                                                                                                      • Slide Number 73
                                                                                                                                                                      • DIC Management Goals
                                                                                                                                                                      • DIC Management and Treatment
                                                                                                                                                                      • DIC Management Strategies
                                                                                                                                                                      • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                      • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                      • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                      • D-dimer FDPs and DIC
                                                                                                                                                                      • D-Dimer and FDPs in DIC
                                                                                                                                                                      • Follow Up of DIC State of Disease
                                                                                                                                                                      • FMD-Dimer in DIC Major Differences
                                                                                                                                                                      • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                      • Slide Number 85
                                                                                                                                                                      • Slide Number 86
                                                                                                                                                                      • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                      • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                      • Slide Number 94
                                                                                                                                                                      • Slide Number 95
                                                                                                                                                                      • Slide Number 96
                                                                                                                                                                      • Slide Number 97
                                                                                                                                                                      • Slide Number 98
                                                                                                                                                                      • Slide Number 99
                                                                                                                                                                      • DIC Case Studies
                                                                                                                                                                      • Case Study 1 - Presentation
                                                                                                                                                                      • Case Study 1 ndash Lab Results
                                                                                                                                                                      • Case Study 1 ndash Microscopy
                                                                                                                                                                      • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                      • Slide Number 105
                                                                                                                                                                      • Slide Number 106
                                                                                                                                                                      • Slide Number 107
                                                                                                                                                                      • Slide Number 108
                                                                                                                                                                      • Slide Number 109
                                                                                                                                                                      • Slide Number 110
                                                                                                                                                                      • Slide Number 111
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                                                                                                                                                                      • Slide Number 113
                                                                                                                                                                      • Slide Number 114
                                                                                                                                                                      • Slide Number 115
                                                                                                                                                                      • Slide Number 116
                                                                                                                                                                      • Slide Number 117
                                                                                                                                                                      • Slide Number 118
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                                                                                                                                                                      • Slide Number 120
                                                                                                                                                                      • Slide Number 121
                                                                                                                                                                      • Slide Number 122
                                                                                                                                                                      • Slide Number 123
                                                                                                                                                                      • Slide Number 124
                                                                                                                                                                      • Slide Number 125
                                                                                                                                                                      • DIC Take Home Messages
                                                                                                                                                                      • Slide Number 127
                                                                                                                                                                      • Slide Number 128

                                                                                                                                                                        of Abnormal Results in Patients with Confirmed and Suspected DIC

                                                                                                                                                                        0

                                                                                                                                                                        20

                                                                                                                                                                        40

                                                                                                                                                                        60

                                                                                                                                                                        80

                                                                                                                                                                        100

                                                                                                                                                                        94 85 90N = 62

                                                                                                                                                                        Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32

                                                                                                                                                                        Positivity of Test Results ISTH Score and Disease State

                                                                                                                                                                        Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                                                        Red bar positive for 2 points of DIC score

                                                                                                                                                                        Pink bar positive for 1-2 points of DIC score

                                                                                                                                                                        HT hematopoietic tumor

                                                                                                                                                                        IF infection

                                                                                                                                                                        SC solid cancer

                                                                                                                                                                        Markers in Patients with or without DIC

                                                                                                                                                                        Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                                                        HT hematopoietic tumorIF infectionSC solid cancer

                                                                                                                                                                        Comparing an Automated FM vs Manual FSP Test

                                                                                                                                                                        Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                                                                                                        Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                                                                                                        Automated (Mitsubishi) vs Automated (Stago)

                                                                                                                                                                        In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                                                                                                        Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                        In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                        In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                        In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                        Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                        No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                                                                                        Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                        Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                        Non Overt DIC Overt DIC

                                                                                                                                                                        AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                                                                                        Trends in Markers of DIC for Different Patients

                                                                                                                                                                        Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                                                                                        Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                                                                                        Trends in Markers of DIC for Different Patients

                                                                                                                                                                        Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                        FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                                                                                        28 day outcome survival

                                                                                                                                                                        28 day outcome death

                                                                                                                                                                        Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                                        Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                                        Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                                                                                        Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                                        Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                                        Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                                                                                        DIC Case Studies

                                                                                                                                                                        Case Study 1 - Presentation

                                                                                                                                                                        18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                                                                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                        Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                                                                        WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                                                                        RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                                                                        Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                                                                        Hematocrit 195 401 ndash 510

                                                                                                                                                                        MCV 95 fL 790 ndash 922 fL

                                                                                                                                                                        MPV 12 fL 94 ndash 124 fL

                                                                                                                                                                        Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                                                                        Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                                                                        Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                                                                        PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                                                                        APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                                                                        Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                                                                        D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                                                                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                        Case Study 1 ndash Microscopy

                                                                                                                                                                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                        Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                                                                        Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                                                                        DIC due to TF release by APL blasts

                                                                                                                                                                        Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                                                                        Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                                                                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                        20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                                                                        Case Study 2 ndash Presentation

                                                                                                                                                                        TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                                                                        PT 30 sec 113 ndash 146 sec

                                                                                                                                                                        APTT 75 sec 25 ndash 34 sec

                                                                                                                                                                        D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                                                                        Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                                                                        pH 728 738 to 742

                                                                                                                                                                        PaO2 570 mmHg 80-100 mmHg

                                                                                                                                                                        WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                                                                        ALT 111 IUL 0ndash34 IUL

                                                                                                                                                                        AST 61 IUL 0ndash34 IUL

                                                                                                                                                                        BUN 303 mgdL 08-13 mgdL

                                                                                                                                                                        Case Study 2 ndash Lab Results

                                                                                                                                                                        Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                                                                        Case Study 2 ndash Diagnosis

                                                                                                                                                                        60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                                                                        Case Study 3 ndash Presentation

                                                                                                                                                                        TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                                                        PT 228 sec 113 ndash 146 sec

                                                                                                                                                                        APTT 45 sec 25 ndash 34 sec

                                                                                                                                                                        D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                                                        Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                                                        FV Normal 70-120

                                                                                                                                                                        FVII Normal 55-170

                                                                                                                                                                        FVIII Normal 60-150

                                                                                                                                                                        Protein C Normal 70-130

                                                                                                                                                                        Hb 134 gdL 14-16 gdL

                                                                                                                                                                        WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                                                        ALT 32 IUL 0ndash34 IUL

                                                                                                                                                                        AST 28 IUL 0ndash34 IUL

                                                                                                                                                                        BUN 09 mgdL 08-13 mgdL

                                                                                                                                                                        Case Study 3 ndash Lab Results

                                                                                                                                                                        Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                                                        Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                                                        Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                                                        Case Study 4 ndash Presentation

                                                                                                                                                                        TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                                                        PT 28 sec 113 ndash 146 sec

                                                                                                                                                                        APTT 71 sec 25 ndash 34 sec

                                                                                                                                                                        D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                                                        Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                                                        FV Normal 70-120

                                                                                                                                                                        FVII Normal 55-170

                                                                                                                                                                        FVIII Normal 60-150

                                                                                                                                                                        Protein C Normal 70-130

                                                                                                                                                                        Hb 158 gdL 14-16 gdL

                                                                                                                                                                        WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                                                        ALT 60 IUL 0ndash34 IUL

                                                                                                                                                                        AST 47 IUL 0ndash34 IUL

                                                                                                                                                                        BUN 38 mgdL 08-13 mgdL

                                                                                                                                                                        Case Study 4 ndash Lab Results

                                                                                                                                                                        Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                                                        Case Study 4 ndash Diagnosis

                                                                                                                                                                        55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                                                        Case Study 5 ndash Presentation

                                                                                                                                                                        Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                        Case Study 5 ndash Lab Results and Time Course

                                                                                                                                                                        Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                        TEST RESULT REFERENCE RANGE

                                                                                                                                                                        Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                                                        PT 215 sec 103 ndash 128 sec

                                                                                                                                                                        APTT 44 sec 26 ndash 36 sec

                                                                                                                                                                        D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                                                        Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                                                        FII FV FVIII Low Not reported (NR)

                                                                                                                                                                        FVII FIX FX vWF Normal NR

                                                                                                                                                                        Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                                                        DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                                                        dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                                                        (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                                                        (D) Illustration demonstrating repair

                                                                                                                                                                        Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                                                        Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                        29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                                        Case Study 6 ndash Presentation

                                                                                                                                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                        Case Study 6 ndash Lab Results

                                                                                                                                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                        TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                                        PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                                        INR 658 1 ndash 125

                                                                                                                                                                        APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                                        D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                                        Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                                        Albumin 28 gdL NR

                                                                                                                                                                        Hb 58 gdL NR

                                                                                                                                                                        LDH 1196 UL NR

                                                                                                                                                                        SGPT 144 IU NR

                                                                                                                                                                        SGOT 88 IU NR

                                                                                                                                                                        Bilirubin 32 mgdL NR

                                                                                                                                                                        DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                                        day postop

                                                                                                                                                                        Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                        HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                                        Case Study 6 ndash Discussion

                                                                                                                                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                        44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                                        Case Study 7 ndash Presentation

                                                                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                        On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                                        Case Study 7 ndash Presentation

                                                                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                        Case Study 7 ndash Lab Results vs Time

                                                                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                        Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                                        Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                        On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                        Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                        DIC Take Home Messages

                                                                                                                                                                        Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                        Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                        DIC

                                                                                                                                                                        Thank you Questions

                                                                                                                                                                        • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                        • Learning Objectives
                                                                                                                                                                        • Slide Number 3
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                                                                                                                                                                        • Wound Sealing
                                                                                                                                                                        • The Three Steps of Hemostasis
                                                                                                                                                                        • Vessel Wall
                                                                                                                                                                        • Slide Number 12
                                                                                                                                                                        • Slide Number 13
                                                                                                                                                                        • Platelet Structure UnactivatedActivated
                                                                                                                                                                        • Primary Hemostasis
                                                                                                                                                                        • Primary Hemostasis Assays
                                                                                                                                                                        • Slide Number 17
                                                                                                                                                                        • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                        • Slide Number 19
                                                                                                                                                                        • Coagulation factors
                                                                                                                                                                        • Coagulation Assay Mechanisms
                                                                                                                                                                        • Slide Number 22
                                                                                                                                                                        • Fibrin Formation
                                                                                                                                                                        • Slide Number 24
                                                                                                                                                                        • Fibrinolysis Overview
                                                                                                                                                                        • Fibrinolysis Overview
                                                                                                                                                                        • Slide Number 27
                                                                                                                                                                        • Fibrinolysis Releases D-dimers
                                                                                                                                                                        • Basic Pathophysiology of DIC
                                                                                                                                                                        • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                        • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                        • Clinical Conditions Associated With DIC
                                                                                                                                                                        • Frequency of DIC in Selected Disease States
                                                                                                                                                                        • Underlying Diseases in DIC Patients
                                                                                                                                                                        • Slide Number 36
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                                                                                                                                                                        • Pathophysiology of DIC
                                                                                                                                                                        • Pathogenesis of DIC in Sepsis
                                                                                                                                                                        • Host Response in Severe Sepsis
                                                                                                                                                                        • Organ Failure in Severe Sepsis
                                                                                                                                                                        • Mechanism of DIC in Organ Failure
                                                                                                                                                                        • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                        • Slide Number 47
                                                                                                                                                                        • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                        • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                        • Mechanism of DIC
                                                                                                                                                                        • Pathophysiology of DIC
                                                                                                                                                                        • Pathophysiology of DIC - Mechanism
                                                                                                                                                                        • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                        • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                        • Pathophysiology of Overt DIC
                                                                                                                                                                        • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                        • Slide Number 57
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                                                                                                                                                                        • Slide Number 61
                                                                                                                                                                        • BREAK
                                                                                                                                                                        • Diagnostic and Management Approach for DIC
                                                                                                                                                                        • Diagnosis of DIC
                                                                                                                                                                        • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                        • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                        • Slide Number 67
                                                                                                                                                                        • Slide Number 68
                                                                                                                                                                        • British Journal of Haematology Overt DIC Score
                                                                                                                                                                        • Slide Number 70
                                                                                                                                                                        • Slide Number 71
                                                                                                                                                                        • Slide Number 72
                                                                                                                                                                        • Slide Number 73
                                                                                                                                                                        • DIC Management Goals
                                                                                                                                                                        • DIC Management and Treatment
                                                                                                                                                                        • DIC Management Strategies
                                                                                                                                                                        • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                        • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                        • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                        • D-dimer FDPs and DIC
                                                                                                                                                                        • D-Dimer and FDPs in DIC
                                                                                                                                                                        • Follow Up of DIC State of Disease
                                                                                                                                                                        • FMD-Dimer in DIC Major Differences
                                                                                                                                                                        • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                        • Slide Number 85
                                                                                                                                                                        • Slide Number 86
                                                                                                                                                                        • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                        • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                        • Slide Number 94
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                                                                                                                                                                        • Slide Number 98
                                                                                                                                                                        • Slide Number 99
                                                                                                                                                                        • DIC Case Studies
                                                                                                                                                                        • Case Study 1 - Presentation
                                                                                                                                                                        • Case Study 1 ndash Lab Results
                                                                                                                                                                        • Case Study 1 ndash Microscopy
                                                                                                                                                                        • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                        • Slide Number 105
                                                                                                                                                                        • Slide Number 106
                                                                                                                                                                        • Slide Number 107
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                                                                                                                                                                        • Slide Number 123
                                                                                                                                                                        • Slide Number 124
                                                                                                                                                                        • Slide Number 125
                                                                                                                                                                        • DIC Take Home Messages
                                                                                                                                                                        • Slide Number 127
                                                                                                                                                                        • Slide Number 128

                                                                                                                                                                          Positivity of Test Results ISTH Score and Disease State

                                                                                                                                                                          Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                                                          Red bar positive for 2 points of DIC score

                                                                                                                                                                          Pink bar positive for 1-2 points of DIC score

                                                                                                                                                                          HT hematopoietic tumor

                                                                                                                                                                          IF infection

                                                                                                                                                                          SC solid cancer

                                                                                                                                                                          Markers in Patients with or without DIC

                                                                                                                                                                          Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                                                          HT hematopoietic tumorIF infectionSC solid cancer

                                                                                                                                                                          Comparing an Automated FM vs Manual FSP Test

                                                                                                                                                                          Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                                                                                                          Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                                                                                                          Automated (Mitsubishi) vs Automated (Stago)

                                                                                                                                                                          In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                                                                                                          Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                          In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                                                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                          In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                                                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                          In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                                                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                          Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                          No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                                                                                          Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                          Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                          Non Overt DIC Overt DIC

                                                                                                                                                                          AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                                                                                          Trends in Markers of DIC for Different Patients

                                                                                                                                                                          Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                                                                                          Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                                                                                          Trends in Markers of DIC for Different Patients

                                                                                                                                                                          Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                          FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                                                                                          28 day outcome survival

                                                                                                                                                                          28 day outcome death

                                                                                                                                                                          Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                                          Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                                          Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                                                                                          Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                                          Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                                          Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                                                                                          DIC Case Studies

                                                                                                                                                                          Case Study 1 - Presentation

                                                                                                                                                                          18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                                                                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                          Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                                                                          WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                                                                          RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                                                                          Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                                                                          Hematocrit 195 401 ndash 510

                                                                                                                                                                          MCV 95 fL 790 ndash 922 fL

                                                                                                                                                                          MPV 12 fL 94 ndash 124 fL

                                                                                                                                                                          Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                                                                          Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                                                                          Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                                                                          PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                                                                          APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                                                                          Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                                                                          D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                                                                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                          Case Study 1 ndash Microscopy

                                                                                                                                                                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                          Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                                                                          Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                                                                          DIC due to TF release by APL blasts

                                                                                                                                                                          Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                                                                          Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                                                                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                          20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                                                                          Case Study 2 ndash Presentation

                                                                                                                                                                          TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                                                                          PT 30 sec 113 ndash 146 sec

                                                                                                                                                                          APTT 75 sec 25 ndash 34 sec

                                                                                                                                                                          D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                                                                          Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                                                                          pH 728 738 to 742

                                                                                                                                                                          PaO2 570 mmHg 80-100 mmHg

                                                                                                                                                                          WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                                                                          ALT 111 IUL 0ndash34 IUL

                                                                                                                                                                          AST 61 IUL 0ndash34 IUL

                                                                                                                                                                          BUN 303 mgdL 08-13 mgdL

                                                                                                                                                                          Case Study 2 ndash Lab Results

                                                                                                                                                                          Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                                                                          Case Study 2 ndash Diagnosis

                                                                                                                                                                          60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                                                                          Case Study 3 ndash Presentation

                                                                                                                                                                          TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                                                          PT 228 sec 113 ndash 146 sec

                                                                                                                                                                          APTT 45 sec 25 ndash 34 sec

                                                                                                                                                                          D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                                                          Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                                                          FV Normal 70-120

                                                                                                                                                                          FVII Normal 55-170

                                                                                                                                                                          FVIII Normal 60-150

                                                                                                                                                                          Protein C Normal 70-130

                                                                                                                                                                          Hb 134 gdL 14-16 gdL

                                                                                                                                                                          WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                                                          ALT 32 IUL 0ndash34 IUL

                                                                                                                                                                          AST 28 IUL 0ndash34 IUL

                                                                                                                                                                          BUN 09 mgdL 08-13 mgdL

                                                                                                                                                                          Case Study 3 ndash Lab Results

                                                                                                                                                                          Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                                                          Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                                                          Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                                                          Case Study 4 ndash Presentation

                                                                                                                                                                          TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                                                          PT 28 sec 113 ndash 146 sec

                                                                                                                                                                          APTT 71 sec 25 ndash 34 sec

                                                                                                                                                                          D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                                                          Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                                                          FV Normal 70-120

                                                                                                                                                                          FVII Normal 55-170

                                                                                                                                                                          FVIII Normal 60-150

                                                                                                                                                                          Protein C Normal 70-130

                                                                                                                                                                          Hb 158 gdL 14-16 gdL

                                                                                                                                                                          WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                                                          ALT 60 IUL 0ndash34 IUL

                                                                                                                                                                          AST 47 IUL 0ndash34 IUL

                                                                                                                                                                          BUN 38 mgdL 08-13 mgdL

                                                                                                                                                                          Case Study 4 ndash Lab Results

                                                                                                                                                                          Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                                                          Case Study 4 ndash Diagnosis

                                                                                                                                                                          55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                                                          Case Study 5 ndash Presentation

                                                                                                                                                                          Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                          Case Study 5 ndash Lab Results and Time Course

                                                                                                                                                                          Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                          TEST RESULT REFERENCE RANGE

                                                                                                                                                                          Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                                                          PT 215 sec 103 ndash 128 sec

                                                                                                                                                                          APTT 44 sec 26 ndash 36 sec

                                                                                                                                                                          D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                                                          Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                                                          FII FV FVIII Low Not reported (NR)

                                                                                                                                                                          FVII FIX FX vWF Normal NR

                                                                                                                                                                          Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                                                          DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                                                          dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                                                          (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                                                          (D) Illustration demonstrating repair

                                                                                                                                                                          Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                                                          Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                          29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                                          Case Study 6 ndash Presentation

                                                                                                                                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                          Case Study 6 ndash Lab Results

                                                                                                                                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                          TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                                          PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                                          INR 658 1 ndash 125

                                                                                                                                                                          APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                                          D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                                          Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                                          Albumin 28 gdL NR

                                                                                                                                                                          Hb 58 gdL NR

                                                                                                                                                                          LDH 1196 UL NR

                                                                                                                                                                          SGPT 144 IU NR

                                                                                                                                                                          SGOT 88 IU NR

                                                                                                                                                                          Bilirubin 32 mgdL NR

                                                                                                                                                                          DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                                          day postop

                                                                                                                                                                          Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                          HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                                          Case Study 6 ndash Discussion

                                                                                                                                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                          44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                                          Case Study 7 ndash Presentation

                                                                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                          On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                                          Case Study 7 ndash Presentation

                                                                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                          Case Study 7 ndash Lab Results vs Time

                                                                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                          Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                                          Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                          On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                          Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                          DIC Take Home Messages

                                                                                                                                                                          Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                          Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                          DIC

                                                                                                                                                                          Thank you Questions

                                                                                                                                                                          • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                          • Learning Objectives
                                                                                                                                                                          • Slide Number 3
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                                                                                                                                                                          • Slide Number 8
                                                                                                                                                                          • Wound Sealing
                                                                                                                                                                          • The Three Steps of Hemostasis
                                                                                                                                                                          • Vessel Wall
                                                                                                                                                                          • Slide Number 12
                                                                                                                                                                          • Slide Number 13
                                                                                                                                                                          • Platelet Structure UnactivatedActivated
                                                                                                                                                                          • Primary Hemostasis
                                                                                                                                                                          • Primary Hemostasis Assays
                                                                                                                                                                          • Slide Number 17
                                                                                                                                                                          • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                          • Slide Number 19
                                                                                                                                                                          • Coagulation factors
                                                                                                                                                                          • Coagulation Assay Mechanisms
                                                                                                                                                                          • Slide Number 22
                                                                                                                                                                          • Fibrin Formation
                                                                                                                                                                          • Slide Number 24
                                                                                                                                                                          • Fibrinolysis Overview
                                                                                                                                                                          • Fibrinolysis Overview
                                                                                                                                                                          • Slide Number 27
                                                                                                                                                                          • Fibrinolysis Releases D-dimers
                                                                                                                                                                          • Basic Pathophysiology of DIC
                                                                                                                                                                          • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                          • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                          • Clinical Conditions Associated With DIC
                                                                                                                                                                          • Frequency of DIC in Selected Disease States
                                                                                                                                                                          • Underlying Diseases in DIC Patients
                                                                                                                                                                          • Slide Number 36
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                                                                                                                                                                          • Slide Number 39
                                                                                                                                                                          • Pathophysiology of DIC
                                                                                                                                                                          • Pathogenesis of DIC in Sepsis
                                                                                                                                                                          • Host Response in Severe Sepsis
                                                                                                                                                                          • Organ Failure in Severe Sepsis
                                                                                                                                                                          • Mechanism of DIC in Organ Failure
                                                                                                                                                                          • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                          • Slide Number 47
                                                                                                                                                                          • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                          • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                          • Mechanism of DIC
                                                                                                                                                                          • Pathophysiology of DIC
                                                                                                                                                                          • Pathophysiology of DIC - Mechanism
                                                                                                                                                                          • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                          • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                          • Pathophysiology of Overt DIC
                                                                                                                                                                          • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                          • Slide Number 57
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                                                                                                                                                                          • Slide Number 60
                                                                                                                                                                          • Slide Number 61
                                                                                                                                                                          • BREAK
                                                                                                                                                                          • Diagnostic and Management Approach for DIC
                                                                                                                                                                          • Diagnosis of DIC
                                                                                                                                                                          • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                          • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                          • Slide Number 67
                                                                                                                                                                          • Slide Number 68
                                                                                                                                                                          • British Journal of Haematology Overt DIC Score
                                                                                                                                                                          • Slide Number 70
                                                                                                                                                                          • Slide Number 71
                                                                                                                                                                          • Slide Number 72
                                                                                                                                                                          • Slide Number 73
                                                                                                                                                                          • DIC Management Goals
                                                                                                                                                                          • DIC Management and Treatment
                                                                                                                                                                          • DIC Management Strategies
                                                                                                                                                                          • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                          • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                          • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                          • D-dimer FDPs and DIC
                                                                                                                                                                          • D-Dimer and FDPs in DIC
                                                                                                                                                                          • Follow Up of DIC State of Disease
                                                                                                                                                                          • FMD-Dimer in DIC Major Differences
                                                                                                                                                                          • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                          • Slide Number 85
                                                                                                                                                                          • Slide Number 86
                                                                                                                                                                          • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                          • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                          • Slide Number 94
                                                                                                                                                                          • Slide Number 95
                                                                                                                                                                          • Slide Number 96
                                                                                                                                                                          • Slide Number 97
                                                                                                                                                                          • Slide Number 98
                                                                                                                                                                          • Slide Number 99
                                                                                                                                                                          • DIC Case Studies
                                                                                                                                                                          • Case Study 1 - Presentation
                                                                                                                                                                          • Case Study 1 ndash Lab Results
                                                                                                                                                                          • Case Study 1 ndash Microscopy
                                                                                                                                                                          • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                          • Slide Number 105
                                                                                                                                                                          • Slide Number 106
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                                                                                                                                                                          • Slide Number 122
                                                                                                                                                                          • Slide Number 123
                                                                                                                                                                          • Slide Number 124
                                                                                                                                                                          • Slide Number 125
                                                                                                                                                                          • DIC Take Home Messages
                                                                                                                                                                          • Slide Number 127
                                                                                                                                                                          • Slide Number 128

                                                                                                                                                                            Markers in Patients with or without DIC

                                                                                                                                                                            Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52

                                                                                                                                                                            HT hematopoietic tumorIF infectionSC solid cancer

                                                                                                                                                                            Comparing an Automated FM vs Manual FSP Test

                                                                                                                                                                            Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                                                                                                            Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                                                                                                            Automated (Mitsubishi) vs Automated (Stago)

                                                                                                                                                                            In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                                                                                                            Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                            In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                                                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                            In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                                                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                            In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                                                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                            Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                            Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                            No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                                                                                            Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                            Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                            Non Overt DIC Overt DIC

                                                                                                                                                                            AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                                                                                            Trends in Markers of DIC for Different Patients

                                                                                                                                                                            Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                                                                                            Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                                                                                            Trends in Markers of DIC for Different Patients

                                                                                                                                                                            Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                            FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                                                                                            28 day outcome survival

                                                                                                                                                                            28 day outcome death

                                                                                                                                                                            Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                                            Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                                            Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                                                                                            Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                                            Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                                            Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                                                                                            DIC Case Studies

                                                                                                                                                                            Case Study 1 - Presentation

                                                                                                                                                                            18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                                                                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                            Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                                                                            WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                                                                            RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                                                                            Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                                                                            Hematocrit 195 401 ndash 510

                                                                                                                                                                            MCV 95 fL 790 ndash 922 fL

                                                                                                                                                                            MPV 12 fL 94 ndash 124 fL

                                                                                                                                                                            Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                                                                            Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                                                                            Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                                                                            PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                                                                            APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                                                                            Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                                                                            D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                                                                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                            Case Study 1 ndash Microscopy

                                                                                                                                                                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                            Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                                                                            Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                                                                            DIC due to TF release by APL blasts

                                                                                                                                                                            Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                                                                            Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                                                                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                            20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                                                                            Case Study 2 ndash Presentation

                                                                                                                                                                            TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                                                                            PT 30 sec 113 ndash 146 sec

                                                                                                                                                                            APTT 75 sec 25 ndash 34 sec

                                                                                                                                                                            D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                                                                            Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                                                                            pH 728 738 to 742

                                                                                                                                                                            PaO2 570 mmHg 80-100 mmHg

                                                                                                                                                                            WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                                                                            ALT 111 IUL 0ndash34 IUL

                                                                                                                                                                            AST 61 IUL 0ndash34 IUL

                                                                                                                                                                            BUN 303 mgdL 08-13 mgdL

                                                                                                                                                                            Case Study 2 ndash Lab Results

                                                                                                                                                                            Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                                                                            Case Study 2 ndash Diagnosis

                                                                                                                                                                            60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                                                                            Case Study 3 ndash Presentation

                                                                                                                                                                            TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                                                            PT 228 sec 113 ndash 146 sec

                                                                                                                                                                            APTT 45 sec 25 ndash 34 sec

                                                                                                                                                                            D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                                                            Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                                                            FV Normal 70-120

                                                                                                                                                                            FVII Normal 55-170

                                                                                                                                                                            FVIII Normal 60-150

                                                                                                                                                                            Protein C Normal 70-130

                                                                                                                                                                            Hb 134 gdL 14-16 gdL

                                                                                                                                                                            WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                                                            ALT 32 IUL 0ndash34 IUL

                                                                                                                                                                            AST 28 IUL 0ndash34 IUL

                                                                                                                                                                            BUN 09 mgdL 08-13 mgdL

                                                                                                                                                                            Case Study 3 ndash Lab Results

                                                                                                                                                                            Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                                                            Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                                                            Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                                                            Case Study 4 ndash Presentation

                                                                                                                                                                            TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                                                            PT 28 sec 113 ndash 146 sec

                                                                                                                                                                            APTT 71 sec 25 ndash 34 sec

                                                                                                                                                                            D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                                                            Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                                                            FV Normal 70-120

                                                                                                                                                                            FVII Normal 55-170

                                                                                                                                                                            FVIII Normal 60-150

                                                                                                                                                                            Protein C Normal 70-130

                                                                                                                                                                            Hb 158 gdL 14-16 gdL

                                                                                                                                                                            WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                                                            ALT 60 IUL 0ndash34 IUL

                                                                                                                                                                            AST 47 IUL 0ndash34 IUL

                                                                                                                                                                            BUN 38 mgdL 08-13 mgdL

                                                                                                                                                                            Case Study 4 ndash Lab Results

                                                                                                                                                                            Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                                                            Case Study 4 ndash Diagnosis

                                                                                                                                                                            55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                                                            Case Study 5 ndash Presentation

                                                                                                                                                                            Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                            Case Study 5 ndash Lab Results and Time Course

                                                                                                                                                                            Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                            TEST RESULT REFERENCE RANGE

                                                                                                                                                                            Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                                                            PT 215 sec 103 ndash 128 sec

                                                                                                                                                                            APTT 44 sec 26 ndash 36 sec

                                                                                                                                                                            D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                                                            Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                                                            FII FV FVIII Low Not reported (NR)

                                                                                                                                                                            FVII FIX FX vWF Normal NR

                                                                                                                                                                            Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                                                            DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                                                            dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                                                            (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                                                            (D) Illustration demonstrating repair

                                                                                                                                                                            Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                                                            Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                            29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                                            Case Study 6 ndash Presentation

                                                                                                                                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                            Case Study 6 ndash Lab Results

                                                                                                                                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                            TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                                            PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                                            INR 658 1 ndash 125

                                                                                                                                                                            APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                                            D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                                            Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                                            Albumin 28 gdL NR

                                                                                                                                                                            Hb 58 gdL NR

                                                                                                                                                                            LDH 1196 UL NR

                                                                                                                                                                            SGPT 144 IU NR

                                                                                                                                                                            SGOT 88 IU NR

                                                                                                                                                                            Bilirubin 32 mgdL NR

                                                                                                                                                                            DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                                            day postop

                                                                                                                                                                            Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                            HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                                            Case Study 6 ndash Discussion

                                                                                                                                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                            44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                                            Case Study 7 ndash Presentation

                                                                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                            On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                                            Case Study 7 ndash Presentation

                                                                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                            Case Study 7 ndash Lab Results vs Time

                                                                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                            Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                                            Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                            On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                            Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                            DIC Take Home Messages

                                                                                                                                                                            Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                            Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                            DIC

                                                                                                                                                                            Thank you Questions

                                                                                                                                                                            • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                            • Learning Objectives
                                                                                                                                                                            • Slide Number 3
                                                                                                                                                                            • Slide Number 4
                                                                                                                                                                            • Slide Number 5
                                                                                                                                                                            • Slide Number 6
                                                                                                                                                                            • Slide Number 7
                                                                                                                                                                            • Slide Number 8
                                                                                                                                                                            • Wound Sealing
                                                                                                                                                                            • The Three Steps of Hemostasis
                                                                                                                                                                            • Vessel Wall
                                                                                                                                                                            • Slide Number 12
                                                                                                                                                                            • Slide Number 13
                                                                                                                                                                            • Platelet Structure UnactivatedActivated
                                                                                                                                                                            • Primary Hemostasis
                                                                                                                                                                            • Primary Hemostasis Assays
                                                                                                                                                                            • Slide Number 17
                                                                                                                                                                            • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                            • Slide Number 19
                                                                                                                                                                            • Coagulation factors
                                                                                                                                                                            • Coagulation Assay Mechanisms
                                                                                                                                                                            • Slide Number 22
                                                                                                                                                                            • Fibrin Formation
                                                                                                                                                                            • Slide Number 24
                                                                                                                                                                            • Fibrinolysis Overview
                                                                                                                                                                            • Fibrinolysis Overview
                                                                                                                                                                            • Slide Number 27
                                                                                                                                                                            • Fibrinolysis Releases D-dimers
                                                                                                                                                                            • Basic Pathophysiology of DIC
                                                                                                                                                                            • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                            • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                            • Clinical Conditions Associated With DIC
                                                                                                                                                                            • Frequency of DIC in Selected Disease States
                                                                                                                                                                            • Underlying Diseases in DIC Patients
                                                                                                                                                                            • Slide Number 36
                                                                                                                                                                            • Slide Number 37
                                                                                                                                                                            • Slide Number 38
                                                                                                                                                                            • Slide Number 39
                                                                                                                                                                            • Pathophysiology of DIC
                                                                                                                                                                            • Pathogenesis of DIC in Sepsis
                                                                                                                                                                            • Host Response in Severe Sepsis
                                                                                                                                                                            • Organ Failure in Severe Sepsis
                                                                                                                                                                            • Mechanism of DIC in Organ Failure
                                                                                                                                                                            • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                            • Slide Number 47
                                                                                                                                                                            • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                            • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                            • Mechanism of DIC
                                                                                                                                                                            • Pathophysiology of DIC
                                                                                                                                                                            • Pathophysiology of DIC - Mechanism
                                                                                                                                                                            • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                            • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                            • Pathophysiology of Overt DIC
                                                                                                                                                                            • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                            • Slide Number 57
                                                                                                                                                                            • Slide Number 58
                                                                                                                                                                            • Slide Number 59
                                                                                                                                                                            • Slide Number 60
                                                                                                                                                                            • Slide Number 61
                                                                                                                                                                            • BREAK
                                                                                                                                                                            • Diagnostic and Management Approach for DIC
                                                                                                                                                                            • Diagnosis of DIC
                                                                                                                                                                            • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                            • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                            • Slide Number 67
                                                                                                                                                                            • Slide Number 68
                                                                                                                                                                            • British Journal of Haematology Overt DIC Score
                                                                                                                                                                            • Slide Number 70
                                                                                                                                                                            • Slide Number 71
                                                                                                                                                                            • Slide Number 72
                                                                                                                                                                            • Slide Number 73
                                                                                                                                                                            • DIC Management Goals
                                                                                                                                                                            • DIC Management and Treatment
                                                                                                                                                                            • DIC Management Strategies
                                                                                                                                                                            • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                            • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                            • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                            • D-dimer FDPs and DIC
                                                                                                                                                                            • D-Dimer and FDPs in DIC
                                                                                                                                                                            • Follow Up of DIC State of Disease
                                                                                                                                                                            • FMD-Dimer in DIC Major Differences
                                                                                                                                                                            • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                            • Slide Number 85
                                                                                                                                                                            • Slide Number 86
                                                                                                                                                                            • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                            • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                            • Slide Number 94
                                                                                                                                                                            • Slide Number 95
                                                                                                                                                                            • Slide Number 96
                                                                                                                                                                            • Slide Number 97
                                                                                                                                                                            • Slide Number 98
                                                                                                                                                                            • Slide Number 99
                                                                                                                                                                            • DIC Case Studies
                                                                                                                                                                            • Case Study 1 - Presentation
                                                                                                                                                                            • Case Study 1 ndash Lab Results
                                                                                                                                                                            • Case Study 1 ndash Microscopy
                                                                                                                                                                            • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                            • Slide Number 105
                                                                                                                                                                            • Slide Number 106
                                                                                                                                                                            • Slide Number 107
                                                                                                                                                                            • Slide Number 108
                                                                                                                                                                            • Slide Number 109
                                                                                                                                                                            • Slide Number 110
                                                                                                                                                                            • Slide Number 111
                                                                                                                                                                            • Slide Number 112
                                                                                                                                                                            • Slide Number 113
                                                                                                                                                                            • Slide Number 114
                                                                                                                                                                            • Slide Number 115
                                                                                                                                                                            • Slide Number 116
                                                                                                                                                                            • Slide Number 117
                                                                                                                                                                            • Slide Number 118
                                                                                                                                                                            • Slide Number 119
                                                                                                                                                                            • Slide Number 120
                                                                                                                                                                            • Slide Number 121
                                                                                                                                                                            • Slide Number 122
                                                                                                                                                                            • Slide Number 123
                                                                                                                                                                            • Slide Number 124
                                                                                                                                                                            • Slide Number 125
                                                                                                                                                                            • DIC Take Home Messages
                                                                                                                                                                            • Slide Number 127
                                                                                                                                                                            • Slide Number 128

                                                                                                                                                                              Comparing an Automated FM vs Manual FSP Test

                                                                                                                                                                              Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71

                                                                                                                                                                              Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)

                                                                                                                                                                              Automated (Mitsubishi) vs Automated (Stago)

                                                                                                                                                                              In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago

                                                                                                                                                                              Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                              In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                                                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                              In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                                                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                              In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                                                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                              Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                              Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                              No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                                                                                              Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                              Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                              Non Overt DIC Overt DIC

                                                                                                                                                                              AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                                                                                              Trends in Markers of DIC for Different Patients

                                                                                                                                                                              Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                                                                                              Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                                                                                              Trends in Markers of DIC for Different Patients

                                                                                                                                                                              Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                              FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                                                                                              28 day outcome survival

                                                                                                                                                                              28 day outcome death

                                                                                                                                                                              Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                                              Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                                              Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                                                                                              Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                                              Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                                              Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                                                                                              DIC Case Studies

                                                                                                                                                                              Case Study 1 - Presentation

                                                                                                                                                                              18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                                                                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                              Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                                                                              WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                                                                              RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                                                                              Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                                                                              Hematocrit 195 401 ndash 510

                                                                                                                                                                              MCV 95 fL 790 ndash 922 fL

                                                                                                                                                                              MPV 12 fL 94 ndash 124 fL

                                                                                                                                                                              Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                                                                              Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                                                                              Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                                                                              PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                                                                              APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                                                                              Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                                                                              D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                                                                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                              Case Study 1 ndash Microscopy

                                                                                                                                                                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                              Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                                                                              Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                                                                              DIC due to TF release by APL blasts

                                                                                                                                                                              Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                                                                              Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                                                                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                              20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                                                                              Case Study 2 ndash Presentation

                                                                                                                                                                              TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                                                                              PT 30 sec 113 ndash 146 sec

                                                                                                                                                                              APTT 75 sec 25 ndash 34 sec

                                                                                                                                                                              D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                                                                              Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                                                                              pH 728 738 to 742

                                                                                                                                                                              PaO2 570 mmHg 80-100 mmHg

                                                                                                                                                                              WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                                                                              ALT 111 IUL 0ndash34 IUL

                                                                                                                                                                              AST 61 IUL 0ndash34 IUL

                                                                                                                                                                              BUN 303 mgdL 08-13 mgdL

                                                                                                                                                                              Case Study 2 ndash Lab Results

                                                                                                                                                                              Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                                                                              Case Study 2 ndash Diagnosis

                                                                                                                                                                              60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                                                                              Case Study 3 ndash Presentation

                                                                                                                                                                              TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                                                              PT 228 sec 113 ndash 146 sec

                                                                                                                                                                              APTT 45 sec 25 ndash 34 sec

                                                                                                                                                                              D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                                                              Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                                                              FV Normal 70-120

                                                                                                                                                                              FVII Normal 55-170

                                                                                                                                                                              FVIII Normal 60-150

                                                                                                                                                                              Protein C Normal 70-130

                                                                                                                                                                              Hb 134 gdL 14-16 gdL

                                                                                                                                                                              WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                                                              ALT 32 IUL 0ndash34 IUL

                                                                                                                                                                              AST 28 IUL 0ndash34 IUL

                                                                                                                                                                              BUN 09 mgdL 08-13 mgdL

                                                                                                                                                                              Case Study 3 ndash Lab Results

                                                                                                                                                                              Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                                                              Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                                                              Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                                                              Case Study 4 ndash Presentation

                                                                                                                                                                              TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                                                              PT 28 sec 113 ndash 146 sec

                                                                                                                                                                              APTT 71 sec 25 ndash 34 sec

                                                                                                                                                                              D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                                                              Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                                                              FV Normal 70-120

                                                                                                                                                                              FVII Normal 55-170

                                                                                                                                                                              FVIII Normal 60-150

                                                                                                                                                                              Protein C Normal 70-130

                                                                                                                                                                              Hb 158 gdL 14-16 gdL

                                                                                                                                                                              WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                                                              ALT 60 IUL 0ndash34 IUL

                                                                                                                                                                              AST 47 IUL 0ndash34 IUL

                                                                                                                                                                              BUN 38 mgdL 08-13 mgdL

                                                                                                                                                                              Case Study 4 ndash Lab Results

                                                                                                                                                                              Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                                                              Case Study 4 ndash Diagnosis

                                                                                                                                                                              55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                                                              Case Study 5 ndash Presentation

                                                                                                                                                                              Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                              Case Study 5 ndash Lab Results and Time Course

                                                                                                                                                                              Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                              TEST RESULT REFERENCE RANGE

                                                                                                                                                                              Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                                                              PT 215 sec 103 ndash 128 sec

                                                                                                                                                                              APTT 44 sec 26 ndash 36 sec

                                                                                                                                                                              D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                                                              Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                                                              FII FV FVIII Low Not reported (NR)

                                                                                                                                                                              FVII FIX FX vWF Normal NR

                                                                                                                                                                              Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                                                              DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                                                              dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                                                              (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                                                              (D) Illustration demonstrating repair

                                                                                                                                                                              Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                                                              Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                              29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                                              Case Study 6 ndash Presentation

                                                                                                                                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                              Case Study 6 ndash Lab Results

                                                                                                                                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                              TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                                              PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                                              INR 658 1 ndash 125

                                                                                                                                                                              APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                                              D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                                              Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                                              Albumin 28 gdL NR

                                                                                                                                                                              Hb 58 gdL NR

                                                                                                                                                                              LDH 1196 UL NR

                                                                                                                                                                              SGPT 144 IU NR

                                                                                                                                                                              SGOT 88 IU NR

                                                                                                                                                                              Bilirubin 32 mgdL NR

                                                                                                                                                                              DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                                              day postop

                                                                                                                                                                              Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                              HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                                              Case Study 6 ndash Discussion

                                                                                                                                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                              44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                                              Case Study 7 ndash Presentation

                                                                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                              On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                                              Case Study 7 ndash Presentation

                                                                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                              Case Study 7 ndash Lab Results vs Time

                                                                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                              Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                                              Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                              On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                              Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                              DIC Take Home Messages

                                                                                                                                                                              Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                              Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                              DIC

                                                                                                                                                                              Thank you Questions

                                                                                                                                                                              • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                              • Learning Objectives
                                                                                                                                                                              • Slide Number 3
                                                                                                                                                                              • Slide Number 4
                                                                                                                                                                              • Slide Number 5
                                                                                                                                                                              • Slide Number 6
                                                                                                                                                                              • Slide Number 7
                                                                                                                                                                              • Slide Number 8
                                                                                                                                                                              • Wound Sealing
                                                                                                                                                                              • The Three Steps of Hemostasis
                                                                                                                                                                              • Vessel Wall
                                                                                                                                                                              • Slide Number 12
                                                                                                                                                                              • Slide Number 13
                                                                                                                                                                              • Platelet Structure UnactivatedActivated
                                                                                                                                                                              • Primary Hemostasis
                                                                                                                                                                              • Primary Hemostasis Assays
                                                                                                                                                                              • Slide Number 17
                                                                                                                                                                              • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                              • Slide Number 19
                                                                                                                                                                              • Coagulation factors
                                                                                                                                                                              • Coagulation Assay Mechanisms
                                                                                                                                                                              • Slide Number 22
                                                                                                                                                                              • Fibrin Formation
                                                                                                                                                                              • Slide Number 24
                                                                                                                                                                              • Fibrinolysis Overview
                                                                                                                                                                              • Fibrinolysis Overview
                                                                                                                                                                              • Slide Number 27
                                                                                                                                                                              • Fibrinolysis Releases D-dimers
                                                                                                                                                                              • Basic Pathophysiology of DIC
                                                                                                                                                                              • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                              • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                              • Clinical Conditions Associated With DIC
                                                                                                                                                                              • Frequency of DIC in Selected Disease States
                                                                                                                                                                              • Underlying Diseases in DIC Patients
                                                                                                                                                                              • Slide Number 36
                                                                                                                                                                              • Slide Number 37
                                                                                                                                                                              • Slide Number 38
                                                                                                                                                                              • Slide Number 39
                                                                                                                                                                              • Pathophysiology of DIC
                                                                                                                                                                              • Pathogenesis of DIC in Sepsis
                                                                                                                                                                              • Host Response in Severe Sepsis
                                                                                                                                                                              • Organ Failure in Severe Sepsis
                                                                                                                                                                              • Mechanism of DIC in Organ Failure
                                                                                                                                                                              • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                              • Slide Number 47
                                                                                                                                                                              • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                              • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                              • Mechanism of DIC
                                                                                                                                                                              • Pathophysiology of DIC
                                                                                                                                                                              • Pathophysiology of DIC - Mechanism
                                                                                                                                                                              • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                              • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                              • Pathophysiology of Overt DIC
                                                                                                                                                                              • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                              • Slide Number 57
                                                                                                                                                                              • Slide Number 58
                                                                                                                                                                              • Slide Number 59
                                                                                                                                                                              • Slide Number 60
                                                                                                                                                                              • Slide Number 61
                                                                                                                                                                              • BREAK
                                                                                                                                                                              • Diagnostic and Management Approach for DIC
                                                                                                                                                                              • Diagnosis of DIC
                                                                                                                                                                              • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                              • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                              • Slide Number 67
                                                                                                                                                                              • Slide Number 68
                                                                                                                                                                              • British Journal of Haematology Overt DIC Score
                                                                                                                                                                              • Slide Number 70
                                                                                                                                                                              • Slide Number 71
                                                                                                                                                                              • Slide Number 72
                                                                                                                                                                              • Slide Number 73
                                                                                                                                                                              • DIC Management Goals
                                                                                                                                                                              • DIC Management and Treatment
                                                                                                                                                                              • DIC Management Strategies
                                                                                                                                                                              • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                              • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                              • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                              • D-dimer FDPs and DIC
                                                                                                                                                                              • D-Dimer and FDPs in DIC
                                                                                                                                                                              • Follow Up of DIC State of Disease
                                                                                                                                                                              • FMD-Dimer in DIC Major Differences
                                                                                                                                                                              • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                              • Slide Number 85
                                                                                                                                                                              • Slide Number 86
                                                                                                                                                                              • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                              • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                              • Slide Number 94
                                                                                                                                                                              • Slide Number 95
                                                                                                                                                                              • Slide Number 96
                                                                                                                                                                              • Slide Number 97
                                                                                                                                                                              • Slide Number 98
                                                                                                                                                                              • Slide Number 99
                                                                                                                                                                              • DIC Case Studies
                                                                                                                                                                              • Case Study 1 - Presentation
                                                                                                                                                                              • Case Study 1 ndash Lab Results
                                                                                                                                                                              • Case Study 1 ndash Microscopy
                                                                                                                                                                              • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                              • Slide Number 105
                                                                                                                                                                              • Slide Number 106
                                                                                                                                                                              • Slide Number 107
                                                                                                                                                                              • Slide Number 108
                                                                                                                                                                              • Slide Number 109
                                                                                                                                                                              • Slide Number 110
                                                                                                                                                                              • Slide Number 111
                                                                                                                                                                              • Slide Number 112
                                                                                                                                                                              • Slide Number 113
                                                                                                                                                                              • Slide Number 114
                                                                                                                                                                              • Slide Number 115
                                                                                                                                                                              • Slide Number 116
                                                                                                                                                                              • Slide Number 117
                                                                                                                                                                              • Slide Number 118
                                                                                                                                                                              • Slide Number 119
                                                                                                                                                                              • Slide Number 120
                                                                                                                                                                              • Slide Number 121
                                                                                                                                                                              • Slide Number 122
                                                                                                                                                                              • Slide Number 123
                                                                                                                                                                              • Slide Number 124
                                                                                                                                                                              • Slide Number 125
                                                                                                                                                                              • DIC Take Home Messages
                                                                                                                                                                              • Slide Number 127
                                                                                                                                                                              • Slide Number 128

                                                                                                                                                                                Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                                In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                                                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                                In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                                                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                                In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                                                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                                Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                                Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                                No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                                                                                                Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                                                                                                Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                                Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                                Non Overt DIC Overt DIC

                                                                                                                                                                                AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                                                                                                Trends in Markers of DIC for Different Patients

                                                                                                                                                                                Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                                                                                                Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                                                                                                Trends in Markers of DIC for Different Patients

                                                                                                                                                                                Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                                FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                                                                                                28 day outcome survival

                                                                                                                                                                                28 day outcome death

                                                                                                                                                                                Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                                                Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                                                Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                                                                                                Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                                                Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                                                Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                                                                                                DIC Case Studies

                                                                                                                                                                                Case Study 1 - Presentation

                                                                                                                                                                                18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                                                                                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                                                                                WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                                                                                RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                                                                                Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                                                                                Hematocrit 195 401 ndash 510

                                                                                                                                                                                MCV 95 fL 790 ndash 922 fL

                                                                                                                                                                                MPV 12 fL 94 ndash 124 fL

                                                                                                                                                                                Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                                                                                Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                                                                                Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                                                                                PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                                                                                APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                                                                                Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                                                                                D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                                                                                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                Case Study 1 ndash Microscopy

                                                                                                                                                                                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                                                                                Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                                                                                DIC due to TF release by APL blasts

                                                                                                                                                                                Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                                                                                Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                                                                                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                                                                                Case Study 2 ndash Presentation

                                                                                                                                                                                TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                                                                                PT 30 sec 113 ndash 146 sec

                                                                                                                                                                                APTT 75 sec 25 ndash 34 sec

                                                                                                                                                                                D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                                                                                Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                                                                                pH 728 738 to 742

                                                                                                                                                                                PaO2 570 mmHg 80-100 mmHg

                                                                                                                                                                                WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                ALT 111 IUL 0ndash34 IUL

                                                                                                                                                                                AST 61 IUL 0ndash34 IUL

                                                                                                                                                                                BUN 303 mgdL 08-13 mgdL

                                                                                                                                                                                Case Study 2 ndash Lab Results

                                                                                                                                                                                Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                                                                                Case Study 2 ndash Diagnosis

                                                                                                                                                                                60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                                                                                Case Study 3 ndash Presentation

                                                                                                                                                                                TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                                                                PT 228 sec 113 ndash 146 sec

                                                                                                                                                                                APTT 45 sec 25 ndash 34 sec

                                                                                                                                                                                D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                                                                Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                                                                FV Normal 70-120

                                                                                                                                                                                FVII Normal 55-170

                                                                                                                                                                                FVIII Normal 60-150

                                                                                                                                                                                Protein C Normal 70-130

                                                                                                                                                                                Hb 134 gdL 14-16 gdL

                                                                                                                                                                                WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                ALT 32 IUL 0ndash34 IUL

                                                                                                                                                                                AST 28 IUL 0ndash34 IUL

                                                                                                                                                                                BUN 09 mgdL 08-13 mgdL

                                                                                                                                                                                Case Study 3 ndash Lab Results

                                                                                                                                                                                Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                                                                Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                                                                Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                                                                Case Study 4 ndash Presentation

                                                                                                                                                                                TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                                                                PT 28 sec 113 ndash 146 sec

                                                                                                                                                                                APTT 71 sec 25 ndash 34 sec

                                                                                                                                                                                D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                                                                Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                                                                FV Normal 70-120

                                                                                                                                                                                FVII Normal 55-170

                                                                                                                                                                                FVIII Normal 60-150

                                                                                                                                                                                Protein C Normal 70-130

                                                                                                                                                                                Hb 158 gdL 14-16 gdL

                                                                                                                                                                                WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                ALT 60 IUL 0ndash34 IUL

                                                                                                                                                                                AST 47 IUL 0ndash34 IUL

                                                                                                                                                                                BUN 38 mgdL 08-13 mgdL

                                                                                                                                                                                Case Study 4 ndash Lab Results

                                                                                                                                                                                Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                                                                Case Study 4 ndash Diagnosis

                                                                                                                                                                                55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                                                                Case Study 5 ndash Presentation

                                                                                                                                                                                Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                Case Study 5 ndash Lab Results and Time Course

                                                                                                                                                                                Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                TEST RESULT REFERENCE RANGE

                                                                                                                                                                                Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                                                                PT 215 sec 103 ndash 128 sec

                                                                                                                                                                                APTT 44 sec 26 ndash 36 sec

                                                                                                                                                                                D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                                                                Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                                                                FII FV FVIII Low Not reported (NR)

                                                                                                                                                                                FVII FIX FX vWF Normal NR

                                                                                                                                                                                Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                                                                DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                                                                dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                                                                (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                                                                (D) Illustration demonstrating repair

                                                                                                                                                                                Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                                                                Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                                                Case Study 6 ndash Presentation

                                                                                                                                                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                Case Study 6 ndash Lab Results

                                                                                                                                                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                                                PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                                                INR 658 1 ndash 125

                                                                                                                                                                                APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                                                D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                                                Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                                                Albumin 28 gdL NR

                                                                                                                                                                                Hb 58 gdL NR

                                                                                                                                                                                LDH 1196 UL NR

                                                                                                                                                                                SGPT 144 IU NR

                                                                                                                                                                                SGOT 88 IU NR

                                                                                                                                                                                Bilirubin 32 mgdL NR

                                                                                                                                                                                DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                                                day postop

                                                                                                                                                                                Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                                                Case Study 6 ndash Discussion

                                                                                                                                                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                                                Case Study 7 ndash Presentation

                                                                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                                                Case Study 7 ndash Presentation

                                                                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                Case Study 7 ndash Lab Results vs Time

                                                                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                                                Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                                Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                DIC Take Home Messages

                                                                                                                                                                                Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                                Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                                DIC

                                                                                                                                                                                Thank you Questions

                                                                                                                                                                                • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                                • Learning Objectives
                                                                                                                                                                                • Slide Number 3
                                                                                                                                                                                • Slide Number 4
                                                                                                                                                                                • Slide Number 5
                                                                                                                                                                                • Slide Number 6
                                                                                                                                                                                • Slide Number 7
                                                                                                                                                                                • Slide Number 8
                                                                                                                                                                                • Wound Sealing
                                                                                                                                                                                • The Three Steps of Hemostasis
                                                                                                                                                                                • Vessel Wall
                                                                                                                                                                                • Slide Number 12
                                                                                                                                                                                • Slide Number 13
                                                                                                                                                                                • Platelet Structure UnactivatedActivated
                                                                                                                                                                                • Primary Hemostasis
                                                                                                                                                                                • Primary Hemostasis Assays
                                                                                                                                                                                • Slide Number 17
                                                                                                                                                                                • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                                • Slide Number 19
                                                                                                                                                                                • Coagulation factors
                                                                                                                                                                                • Coagulation Assay Mechanisms
                                                                                                                                                                                • Slide Number 22
                                                                                                                                                                                • Fibrin Formation
                                                                                                                                                                                • Slide Number 24
                                                                                                                                                                                • Fibrinolysis Overview
                                                                                                                                                                                • Fibrinolysis Overview
                                                                                                                                                                                • Slide Number 27
                                                                                                                                                                                • Fibrinolysis Releases D-dimers
                                                                                                                                                                                • Basic Pathophysiology of DIC
                                                                                                                                                                                • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                                • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                                • Clinical Conditions Associated With DIC
                                                                                                                                                                                • Frequency of DIC in Selected Disease States
                                                                                                                                                                                • Underlying Diseases in DIC Patients
                                                                                                                                                                                • Slide Number 36
                                                                                                                                                                                • Slide Number 37
                                                                                                                                                                                • Slide Number 38
                                                                                                                                                                                • Slide Number 39
                                                                                                                                                                                • Pathophysiology of DIC
                                                                                                                                                                                • Pathogenesis of DIC in Sepsis
                                                                                                                                                                                • Host Response in Severe Sepsis
                                                                                                                                                                                • Organ Failure in Severe Sepsis
                                                                                                                                                                                • Mechanism of DIC in Organ Failure
                                                                                                                                                                                • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                                • Slide Number 47
                                                                                                                                                                                • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                                • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                                • Mechanism of DIC
                                                                                                                                                                                • Pathophysiology of DIC
                                                                                                                                                                                • Pathophysiology of DIC - Mechanism
                                                                                                                                                                                • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                                • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                                • Pathophysiology of Overt DIC
                                                                                                                                                                                • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                                • Slide Number 57
                                                                                                                                                                                • Slide Number 58
                                                                                                                                                                                • Slide Number 59
                                                                                                                                                                                • Slide Number 60
                                                                                                                                                                                • Slide Number 61
                                                                                                                                                                                • BREAK
                                                                                                                                                                                • Diagnostic and Management Approach for DIC
                                                                                                                                                                                • Diagnosis of DIC
                                                                                                                                                                                • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                                • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                                • Slide Number 67
                                                                                                                                                                                • Slide Number 68
                                                                                                                                                                                • British Journal of Haematology Overt DIC Score
                                                                                                                                                                                • Slide Number 70
                                                                                                                                                                                • Slide Number 71
                                                                                                                                                                                • Slide Number 72
                                                                                                                                                                                • Slide Number 73
                                                                                                                                                                                • DIC Management Goals
                                                                                                                                                                                • DIC Management and Treatment
                                                                                                                                                                                • DIC Management Strategies
                                                                                                                                                                                • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                                • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                                • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                                • D-dimer FDPs and DIC
                                                                                                                                                                                • D-Dimer and FDPs in DIC
                                                                                                                                                                                • Follow Up of DIC State of Disease
                                                                                                                                                                                • FMD-Dimer in DIC Major Differences
                                                                                                                                                                                • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                                • Slide Number 85
                                                                                                                                                                                • Slide Number 86
                                                                                                                                                                                • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                                • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                • Slide Number 94
                                                                                                                                                                                • Slide Number 95
                                                                                                                                                                                • Slide Number 96
                                                                                                                                                                                • Slide Number 97
                                                                                                                                                                                • Slide Number 98
                                                                                                                                                                                • Slide Number 99
                                                                                                                                                                                • DIC Case Studies
                                                                                                                                                                                • Case Study 1 - Presentation
                                                                                                                                                                                • Case Study 1 ndash Lab Results
                                                                                                                                                                                • Case Study 1 ndash Microscopy
                                                                                                                                                                                • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                                • Slide Number 105
                                                                                                                                                                                • Slide Number 106
                                                                                                                                                                                • Slide Number 107
                                                                                                                                                                                • Slide Number 108
                                                                                                                                                                                • Slide Number 109
                                                                                                                                                                                • Slide Number 110
                                                                                                                                                                                • Slide Number 111
                                                                                                                                                                                • Slide Number 112
                                                                                                                                                                                • Slide Number 113
                                                                                                                                                                                • Slide Number 114
                                                                                                                                                                                • Slide Number 115
                                                                                                                                                                                • Slide Number 116
                                                                                                                                                                                • Slide Number 117
                                                                                                                                                                                • Slide Number 118
                                                                                                                                                                                • Slide Number 119
                                                                                                                                                                                • Slide Number 120
                                                                                                                                                                                • Slide Number 121
                                                                                                                                                                                • Slide Number 122
                                                                                                                                                                                • Slide Number 123
                                                                                                                                                                                • Slide Number 124
                                                                                                                                                                                • Slide Number 125
                                                                                                                                                                                • DIC Take Home Messages
                                                                                                                                                                                • Slide Number 127
                                                                                                                                                                                • Slide Number 128

                                                                                                                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                                  In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                                                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                                  In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                                                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                                  In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                                                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                                  Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                                  Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                                  No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                                                                                                  Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                                                                                                  Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                                  Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                                  Non Overt DIC Overt DIC

                                                                                                                                                                                  AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                                                                                                  Trends in Markers of DIC for Different Patients

                                                                                                                                                                                  Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                                                                                                  Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                                                                                                  Trends in Markers of DIC for Different Patients

                                                                                                                                                                                  Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                                  FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                                                                                                  28 day outcome survival

                                                                                                                                                                                  28 day outcome death

                                                                                                                                                                                  Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                                                  Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                                                  Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                                                                                                  Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                                                  Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                                                  Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                                                                                                  DIC Case Studies

                                                                                                                                                                                  Case Study 1 - Presentation

                                                                                                                                                                                  18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                                                                                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                  Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                                                                                  WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                                                                                  RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                                                                                  Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                                                                                  Hematocrit 195 401 ndash 510

                                                                                                                                                                                  MCV 95 fL 790 ndash 922 fL

                                                                                                                                                                                  MPV 12 fL 94 ndash 124 fL

                                                                                                                                                                                  Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                                                                                  Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                                                                                  Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                                                                                  PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                                                                                  APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                                                                                  Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                                                                                  D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                                                                                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                  Case Study 1 ndash Microscopy

                                                                                                                                                                                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                  Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                                                                                  Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                                                                                  DIC due to TF release by APL blasts

                                                                                                                                                                                  Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                                                                                  Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                                                                                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                  20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                                                                                  Case Study 2 ndash Presentation

                                                                                                                                                                                  TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                                                                                  PT 30 sec 113 ndash 146 sec

                                                                                                                                                                                  APTT 75 sec 25 ndash 34 sec

                                                                                                                                                                                  D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                                                                                  Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                                                                                  pH 728 738 to 742

                                                                                                                                                                                  PaO2 570 mmHg 80-100 mmHg

                                                                                                                                                                                  WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                  ALT 111 IUL 0ndash34 IUL

                                                                                                                                                                                  AST 61 IUL 0ndash34 IUL

                                                                                                                                                                                  BUN 303 mgdL 08-13 mgdL

                                                                                                                                                                                  Case Study 2 ndash Lab Results

                                                                                                                                                                                  Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                                                                                  Case Study 2 ndash Diagnosis

                                                                                                                                                                                  60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                                                                                  Case Study 3 ndash Presentation

                                                                                                                                                                                  TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                                                                  PT 228 sec 113 ndash 146 sec

                                                                                                                                                                                  APTT 45 sec 25 ndash 34 sec

                                                                                                                                                                                  D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                                                                  Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                                                                  FV Normal 70-120

                                                                                                                                                                                  FVII Normal 55-170

                                                                                                                                                                                  FVIII Normal 60-150

                                                                                                                                                                                  Protein C Normal 70-130

                                                                                                                                                                                  Hb 134 gdL 14-16 gdL

                                                                                                                                                                                  WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                  ALT 32 IUL 0ndash34 IUL

                                                                                                                                                                                  AST 28 IUL 0ndash34 IUL

                                                                                                                                                                                  BUN 09 mgdL 08-13 mgdL

                                                                                                                                                                                  Case Study 3 ndash Lab Results

                                                                                                                                                                                  Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                                                                  Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                                                                  Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                                                                  Case Study 4 ndash Presentation

                                                                                                                                                                                  TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                                                                  PT 28 sec 113 ndash 146 sec

                                                                                                                                                                                  APTT 71 sec 25 ndash 34 sec

                                                                                                                                                                                  D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                                                                  Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                                                                  FV Normal 70-120

                                                                                                                                                                                  FVII Normal 55-170

                                                                                                                                                                                  FVIII Normal 60-150

                                                                                                                                                                                  Protein C Normal 70-130

                                                                                                                                                                                  Hb 158 gdL 14-16 gdL

                                                                                                                                                                                  WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                  ALT 60 IUL 0ndash34 IUL

                                                                                                                                                                                  AST 47 IUL 0ndash34 IUL

                                                                                                                                                                                  BUN 38 mgdL 08-13 mgdL

                                                                                                                                                                                  Case Study 4 ndash Lab Results

                                                                                                                                                                                  Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                                                                  Case Study 4 ndash Diagnosis

                                                                                                                                                                                  55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                                                                  Case Study 5 ndash Presentation

                                                                                                                                                                                  Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                  Case Study 5 ndash Lab Results and Time Course

                                                                                                                                                                                  Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                  TEST RESULT REFERENCE RANGE

                                                                                                                                                                                  Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                                                                  PT 215 sec 103 ndash 128 sec

                                                                                                                                                                                  APTT 44 sec 26 ndash 36 sec

                                                                                                                                                                                  D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                                                                  Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                                                                  FII FV FVIII Low Not reported (NR)

                                                                                                                                                                                  FVII FIX FX vWF Normal NR

                                                                                                                                                                                  Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                                                                  DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                                                                  dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                                                                  (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                                                                  (D) Illustration demonstrating repair

                                                                                                                                                                                  Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                                                                  Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                  29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                                                  Case Study 6 ndash Presentation

                                                                                                                                                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                  Case Study 6 ndash Lab Results

                                                                                                                                                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                  TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                                                  PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                                                  INR 658 1 ndash 125

                                                                                                                                                                                  APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                                                  D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                                                  Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                                                  Albumin 28 gdL NR

                                                                                                                                                                                  Hb 58 gdL NR

                                                                                                                                                                                  LDH 1196 UL NR

                                                                                                                                                                                  SGPT 144 IU NR

                                                                                                                                                                                  SGOT 88 IU NR

                                                                                                                                                                                  Bilirubin 32 mgdL NR

                                                                                                                                                                                  DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                                                  day postop

                                                                                                                                                                                  Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                  HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                                                  Case Study 6 ndash Discussion

                                                                                                                                                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                  44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                                                  Case Study 7 ndash Presentation

                                                                                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                  On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                                                  Case Study 7 ndash Presentation

                                                                                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                  Case Study 7 ndash Lab Results vs Time

                                                                                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                  Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                                                  Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                  On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                                  Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                  DIC Take Home Messages

                                                                                                                                                                                  Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                                  Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                                  DIC

                                                                                                                                                                                  Thank you Questions

                                                                                                                                                                                  • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                                  • Learning Objectives
                                                                                                                                                                                  • Slide Number 3
                                                                                                                                                                                  • Slide Number 4
                                                                                                                                                                                  • Slide Number 5
                                                                                                                                                                                  • Slide Number 6
                                                                                                                                                                                  • Slide Number 7
                                                                                                                                                                                  • Slide Number 8
                                                                                                                                                                                  • Wound Sealing
                                                                                                                                                                                  • The Three Steps of Hemostasis
                                                                                                                                                                                  • Vessel Wall
                                                                                                                                                                                  • Slide Number 12
                                                                                                                                                                                  • Slide Number 13
                                                                                                                                                                                  • Platelet Structure UnactivatedActivated
                                                                                                                                                                                  • Primary Hemostasis
                                                                                                                                                                                  • Primary Hemostasis Assays
                                                                                                                                                                                  • Slide Number 17
                                                                                                                                                                                  • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                                  • Slide Number 19
                                                                                                                                                                                  • Coagulation factors
                                                                                                                                                                                  • Coagulation Assay Mechanisms
                                                                                                                                                                                  • Slide Number 22
                                                                                                                                                                                  • Fibrin Formation
                                                                                                                                                                                  • Slide Number 24
                                                                                                                                                                                  • Fibrinolysis Overview
                                                                                                                                                                                  • Fibrinolysis Overview
                                                                                                                                                                                  • Slide Number 27
                                                                                                                                                                                  • Fibrinolysis Releases D-dimers
                                                                                                                                                                                  • Basic Pathophysiology of DIC
                                                                                                                                                                                  • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                                  • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                                  • Clinical Conditions Associated With DIC
                                                                                                                                                                                  • Frequency of DIC in Selected Disease States
                                                                                                                                                                                  • Underlying Diseases in DIC Patients
                                                                                                                                                                                  • Slide Number 36
                                                                                                                                                                                  • Slide Number 37
                                                                                                                                                                                  • Slide Number 38
                                                                                                                                                                                  • Slide Number 39
                                                                                                                                                                                  • Pathophysiology of DIC
                                                                                                                                                                                  • Pathogenesis of DIC in Sepsis
                                                                                                                                                                                  • Host Response in Severe Sepsis
                                                                                                                                                                                  • Organ Failure in Severe Sepsis
                                                                                                                                                                                  • Mechanism of DIC in Organ Failure
                                                                                                                                                                                  • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                                  • Slide Number 47
                                                                                                                                                                                  • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                                  • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                                  • Mechanism of DIC
                                                                                                                                                                                  • Pathophysiology of DIC
                                                                                                                                                                                  • Pathophysiology of DIC - Mechanism
                                                                                                                                                                                  • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                                  • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                                  • Pathophysiology of Overt DIC
                                                                                                                                                                                  • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                                  • Slide Number 57
                                                                                                                                                                                  • Slide Number 58
                                                                                                                                                                                  • Slide Number 59
                                                                                                                                                                                  • Slide Number 60
                                                                                                                                                                                  • Slide Number 61
                                                                                                                                                                                  • BREAK
                                                                                                                                                                                  • Diagnostic and Management Approach for DIC
                                                                                                                                                                                  • Diagnosis of DIC
                                                                                                                                                                                  • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                                  • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                                  • Slide Number 67
                                                                                                                                                                                  • Slide Number 68
                                                                                                                                                                                  • British Journal of Haematology Overt DIC Score
                                                                                                                                                                                  • Slide Number 70
                                                                                                                                                                                  • Slide Number 71
                                                                                                                                                                                  • Slide Number 72
                                                                                                                                                                                  • Slide Number 73
                                                                                                                                                                                  • DIC Management Goals
                                                                                                                                                                                  • DIC Management and Treatment
                                                                                                                                                                                  • DIC Management Strategies
                                                                                                                                                                                  • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                                  • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                                  • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                                  • D-dimer FDPs and DIC
                                                                                                                                                                                  • D-Dimer and FDPs in DIC
                                                                                                                                                                                  • Follow Up of DIC State of Disease
                                                                                                                                                                                  • FMD-Dimer in DIC Major Differences
                                                                                                                                                                                  • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                                  • Slide Number 85
                                                                                                                                                                                  • Slide Number 86
                                                                                                                                                                                  • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                                  • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                  • Slide Number 94
                                                                                                                                                                                  • Slide Number 95
                                                                                                                                                                                  • Slide Number 96
                                                                                                                                                                                  • Slide Number 97
                                                                                                                                                                                  • Slide Number 98
                                                                                                                                                                                  • Slide Number 99
                                                                                                                                                                                  • DIC Case Studies
                                                                                                                                                                                  • Case Study 1 - Presentation
                                                                                                                                                                                  • Case Study 1 ndash Lab Results
                                                                                                                                                                                  • Case Study 1 ndash Microscopy
                                                                                                                                                                                  • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                                  • Slide Number 105
                                                                                                                                                                                  • Slide Number 106
                                                                                                                                                                                  • Slide Number 107
                                                                                                                                                                                  • Slide Number 108
                                                                                                                                                                                  • Slide Number 109
                                                                                                                                                                                  • Slide Number 110
                                                                                                                                                                                  • Slide Number 111
                                                                                                                                                                                  • Slide Number 112
                                                                                                                                                                                  • Slide Number 113
                                                                                                                                                                                  • Slide Number 114
                                                                                                                                                                                  • Slide Number 115
                                                                                                                                                                                  • Slide Number 116
                                                                                                                                                                                  • Slide Number 117
                                                                                                                                                                                  • Slide Number 118
                                                                                                                                                                                  • Slide Number 119
                                                                                                                                                                                  • Slide Number 120
                                                                                                                                                                                  • Slide Number 121
                                                                                                                                                                                  • Slide Number 122
                                                                                                                                                                                  • Slide Number 123
                                                                                                                                                                                  • Slide Number 124
                                                                                                                                                                                  • Slide Number 125
                                                                                                                                                                                  • DIC Take Home Messages
                                                                                                                                                                                  • Slide Number 127
                                                                                                                                                                                  • Slide Number 128

                                                                                                                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                                    In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC

                                                                                                                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                                    In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                                                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                                    In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                                                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                                    Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                                    Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                                    No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                                                                                                    Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                                                                                                    Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                                    Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                                    Non Overt DIC Overt DIC

                                                                                                                                                                                    AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                                                                                                    Trends in Markers of DIC for Different Patients

                                                                                                                                                                                    Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                                                                                                    Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                                                                                                    Trends in Markers of DIC for Different Patients

                                                                                                                                                                                    Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                                    FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                                                                                                    28 day outcome survival

                                                                                                                                                                                    28 day outcome death

                                                                                                                                                                                    Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                                                    Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                                                    Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                                                                                                    Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                                                    Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                                                    Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                                                                                                    DIC Case Studies

                                                                                                                                                                                    Case Study 1 - Presentation

                                                                                                                                                                                    18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                                                                                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                    Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                                                                                    WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                                                                                    RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                                                                                    Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                                                                                    Hematocrit 195 401 ndash 510

                                                                                                                                                                                    MCV 95 fL 790 ndash 922 fL

                                                                                                                                                                                    MPV 12 fL 94 ndash 124 fL

                                                                                                                                                                                    Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                                                                                    Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                                                                                    Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                                                                                    PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                                                                                    APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                                                                                    Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                                                                                    D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                                                                                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                    Case Study 1 ndash Microscopy

                                                                                                                                                                                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                    Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                                                                                    Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                                                                                    DIC due to TF release by APL blasts

                                                                                                                                                                                    Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                                                                                    Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                                                                                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                    20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                                                                                    Case Study 2 ndash Presentation

                                                                                                                                                                                    TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                                                                                    PT 30 sec 113 ndash 146 sec

                                                                                                                                                                                    APTT 75 sec 25 ndash 34 sec

                                                                                                                                                                                    D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                                                                                    Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                                                                                    pH 728 738 to 742

                                                                                                                                                                                    PaO2 570 mmHg 80-100 mmHg

                                                                                                                                                                                    WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                    ALT 111 IUL 0ndash34 IUL

                                                                                                                                                                                    AST 61 IUL 0ndash34 IUL

                                                                                                                                                                                    BUN 303 mgdL 08-13 mgdL

                                                                                                                                                                                    Case Study 2 ndash Lab Results

                                                                                                                                                                                    Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                                                                                    Case Study 2 ndash Diagnosis

                                                                                                                                                                                    60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                                                                                    Case Study 3 ndash Presentation

                                                                                                                                                                                    TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                                                                    PT 228 sec 113 ndash 146 sec

                                                                                                                                                                                    APTT 45 sec 25 ndash 34 sec

                                                                                                                                                                                    D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                                                                    Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                                                                    FV Normal 70-120

                                                                                                                                                                                    FVII Normal 55-170

                                                                                                                                                                                    FVIII Normal 60-150

                                                                                                                                                                                    Protein C Normal 70-130

                                                                                                                                                                                    Hb 134 gdL 14-16 gdL

                                                                                                                                                                                    WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                    ALT 32 IUL 0ndash34 IUL

                                                                                                                                                                                    AST 28 IUL 0ndash34 IUL

                                                                                                                                                                                    BUN 09 mgdL 08-13 mgdL

                                                                                                                                                                                    Case Study 3 ndash Lab Results

                                                                                                                                                                                    Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                                                                    Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                                                                    Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                                                                    Case Study 4 ndash Presentation

                                                                                                                                                                                    TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                                                                    PT 28 sec 113 ndash 146 sec

                                                                                                                                                                                    APTT 71 sec 25 ndash 34 sec

                                                                                                                                                                                    D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                                                                    Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                                                                    FV Normal 70-120

                                                                                                                                                                                    FVII Normal 55-170

                                                                                                                                                                                    FVIII Normal 60-150

                                                                                                                                                                                    Protein C Normal 70-130

                                                                                                                                                                                    Hb 158 gdL 14-16 gdL

                                                                                                                                                                                    WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                    ALT 60 IUL 0ndash34 IUL

                                                                                                                                                                                    AST 47 IUL 0ndash34 IUL

                                                                                                                                                                                    BUN 38 mgdL 08-13 mgdL

                                                                                                                                                                                    Case Study 4 ndash Lab Results

                                                                                                                                                                                    Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                                                                    Case Study 4 ndash Diagnosis

                                                                                                                                                                                    55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                                                                    Case Study 5 ndash Presentation

                                                                                                                                                                                    Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                    Case Study 5 ndash Lab Results and Time Course

                                                                                                                                                                                    Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                    TEST RESULT REFERENCE RANGE

                                                                                                                                                                                    Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                                                                    PT 215 sec 103 ndash 128 sec

                                                                                                                                                                                    APTT 44 sec 26 ndash 36 sec

                                                                                                                                                                                    D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                                                                    Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                                                                    FII FV FVIII Low Not reported (NR)

                                                                                                                                                                                    FVII FIX FX vWF Normal NR

                                                                                                                                                                                    Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                                                                    DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                                                                    dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                                                                    (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                                                                    (D) Illustration demonstrating repair

                                                                                                                                                                                    Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                                                                    Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                    29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                                                    Case Study 6 ndash Presentation

                                                                                                                                                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                    Case Study 6 ndash Lab Results

                                                                                                                                                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                    TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                                                    PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                                                    INR 658 1 ndash 125

                                                                                                                                                                                    APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                                                    D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                                                    Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                                                    Albumin 28 gdL NR

                                                                                                                                                                                    Hb 58 gdL NR

                                                                                                                                                                                    LDH 1196 UL NR

                                                                                                                                                                                    SGPT 144 IU NR

                                                                                                                                                                                    SGOT 88 IU NR

                                                                                                                                                                                    Bilirubin 32 mgdL NR

                                                                                                                                                                                    DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                                                    day postop

                                                                                                                                                                                    Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                    HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                                                    Case Study 6 ndash Discussion

                                                                                                                                                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                    44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                                                    Case Study 7 ndash Presentation

                                                                                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                    On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                                                    Case Study 7 ndash Presentation

                                                                                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                    Case Study 7 ndash Lab Results vs Time

                                                                                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                    Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                                                    Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                    On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                                    Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                    DIC Take Home Messages

                                                                                                                                                                                    Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                                    Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                                    DIC

                                                                                                                                                                                    Thank you Questions

                                                                                                                                                                                    • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                                    • Learning Objectives
                                                                                                                                                                                    • Slide Number 3
                                                                                                                                                                                    • Slide Number 4
                                                                                                                                                                                    • Slide Number 5
                                                                                                                                                                                    • Slide Number 6
                                                                                                                                                                                    • Slide Number 7
                                                                                                                                                                                    • Slide Number 8
                                                                                                                                                                                    • Wound Sealing
                                                                                                                                                                                    • The Three Steps of Hemostasis
                                                                                                                                                                                    • Vessel Wall
                                                                                                                                                                                    • Slide Number 12
                                                                                                                                                                                    • Slide Number 13
                                                                                                                                                                                    • Platelet Structure UnactivatedActivated
                                                                                                                                                                                    • Primary Hemostasis
                                                                                                                                                                                    • Primary Hemostasis Assays
                                                                                                                                                                                    • Slide Number 17
                                                                                                                                                                                    • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                                    • Slide Number 19
                                                                                                                                                                                    • Coagulation factors
                                                                                                                                                                                    • Coagulation Assay Mechanisms
                                                                                                                                                                                    • Slide Number 22
                                                                                                                                                                                    • Fibrin Formation
                                                                                                                                                                                    • Slide Number 24
                                                                                                                                                                                    • Fibrinolysis Overview
                                                                                                                                                                                    • Fibrinolysis Overview
                                                                                                                                                                                    • Slide Number 27
                                                                                                                                                                                    • Fibrinolysis Releases D-dimers
                                                                                                                                                                                    • Basic Pathophysiology of DIC
                                                                                                                                                                                    • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                                    • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                                    • Clinical Conditions Associated With DIC
                                                                                                                                                                                    • Frequency of DIC in Selected Disease States
                                                                                                                                                                                    • Underlying Diseases in DIC Patients
                                                                                                                                                                                    • Slide Number 36
                                                                                                                                                                                    • Slide Number 37
                                                                                                                                                                                    • Slide Number 38
                                                                                                                                                                                    • Slide Number 39
                                                                                                                                                                                    • Pathophysiology of DIC
                                                                                                                                                                                    • Pathogenesis of DIC in Sepsis
                                                                                                                                                                                    • Host Response in Severe Sepsis
                                                                                                                                                                                    • Organ Failure in Severe Sepsis
                                                                                                                                                                                    • Mechanism of DIC in Organ Failure
                                                                                                                                                                                    • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                                    • Slide Number 47
                                                                                                                                                                                    • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                                    • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                                    • Mechanism of DIC
                                                                                                                                                                                    • Pathophysiology of DIC
                                                                                                                                                                                    • Pathophysiology of DIC - Mechanism
                                                                                                                                                                                    • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                                    • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                                    • Pathophysiology of Overt DIC
                                                                                                                                                                                    • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                                    • Slide Number 57
                                                                                                                                                                                    • Slide Number 58
                                                                                                                                                                                    • Slide Number 59
                                                                                                                                                                                    • Slide Number 60
                                                                                                                                                                                    • Slide Number 61
                                                                                                                                                                                    • BREAK
                                                                                                                                                                                    • Diagnostic and Management Approach for DIC
                                                                                                                                                                                    • Diagnosis of DIC
                                                                                                                                                                                    • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                                    • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                                    • Slide Number 67
                                                                                                                                                                                    • Slide Number 68
                                                                                                                                                                                    • British Journal of Haematology Overt DIC Score
                                                                                                                                                                                    • Slide Number 70
                                                                                                                                                                                    • Slide Number 71
                                                                                                                                                                                    • Slide Number 72
                                                                                                                                                                                    • Slide Number 73
                                                                                                                                                                                    • DIC Management Goals
                                                                                                                                                                                    • DIC Management and Treatment
                                                                                                                                                                                    • DIC Management Strategies
                                                                                                                                                                                    • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                                    • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                                    • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                                    • D-dimer FDPs and DIC
                                                                                                                                                                                    • D-Dimer and FDPs in DIC
                                                                                                                                                                                    • Follow Up of DIC State of Disease
                                                                                                                                                                                    • FMD-Dimer in DIC Major Differences
                                                                                                                                                                                    • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                                    • Slide Number 85
                                                                                                                                                                                    • Slide Number 86
                                                                                                                                                                                    • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                                    • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                    • Slide Number 94
                                                                                                                                                                                    • Slide Number 95
                                                                                                                                                                                    • Slide Number 96
                                                                                                                                                                                    • Slide Number 97
                                                                                                                                                                                    • Slide Number 98
                                                                                                                                                                                    • Slide Number 99
                                                                                                                                                                                    • DIC Case Studies
                                                                                                                                                                                    • Case Study 1 - Presentation
                                                                                                                                                                                    • Case Study 1 ndash Lab Results
                                                                                                                                                                                    • Case Study 1 ndash Microscopy
                                                                                                                                                                                    • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                                    • Slide Number 105
                                                                                                                                                                                    • Slide Number 106
                                                                                                                                                                                    • Slide Number 107
                                                                                                                                                                                    • Slide Number 108
                                                                                                                                                                                    • Slide Number 109
                                                                                                                                                                                    • Slide Number 110
                                                                                                                                                                                    • Slide Number 111
                                                                                                                                                                                    • Slide Number 112
                                                                                                                                                                                    • Slide Number 113
                                                                                                                                                                                    • Slide Number 114
                                                                                                                                                                                    • Slide Number 115
                                                                                                                                                                                    • Slide Number 116
                                                                                                                                                                                    • Slide Number 117
                                                                                                                                                                                    • Slide Number 118
                                                                                                                                                                                    • Slide Number 119
                                                                                                                                                                                    • Slide Number 120
                                                                                                                                                                                    • Slide Number 121
                                                                                                                                                                                    • Slide Number 122
                                                                                                                                                                                    • Slide Number 123
                                                                                                                                                                                    • Slide Number 124
                                                                                                                                                                                    • Slide Number 125
                                                                                                                                                                                    • DIC Take Home Messages
                                                                                                                                                                                    • Slide Number 127
                                                                                                                                                                                    • Slide Number 128

                                                                                                                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                                      In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC

                                                                                                                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                                      In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                                                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                                      Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                                      Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                                      No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                                                                                                      Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                                                                                                      Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                                      Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                                      Non Overt DIC Overt DIC

                                                                                                                                                                                      AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                                                                                                      Trends in Markers of DIC for Different Patients

                                                                                                                                                                                      Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                                                                                                      Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                                                                                                      Trends in Markers of DIC for Different Patients

                                                                                                                                                                                      Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                                      FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                                                                                                      28 day outcome survival

                                                                                                                                                                                      28 day outcome death

                                                                                                                                                                                      Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                                                      Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                                                      Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                                                                                                      Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                                                      Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                                                      Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                                                                                                      DIC Case Studies

                                                                                                                                                                                      Case Study 1 - Presentation

                                                                                                                                                                                      18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                                                                                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                      Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                                                                                      WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                                                                                      RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                                                                                      Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                                                                                      Hematocrit 195 401 ndash 510

                                                                                                                                                                                      MCV 95 fL 790 ndash 922 fL

                                                                                                                                                                                      MPV 12 fL 94 ndash 124 fL

                                                                                                                                                                                      Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                                                                                      Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                                                                                      Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                                                                                      PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                                                                                      APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                                                                                      Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                                                                                      D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                                                                                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                      Case Study 1 ndash Microscopy

                                                                                                                                                                                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                      Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                                                                                      Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                                                                                      DIC due to TF release by APL blasts

                                                                                                                                                                                      Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                                                                                      Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                                                                                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                      20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                                                                                      Case Study 2 ndash Presentation

                                                                                                                                                                                      TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                                                                                      PT 30 sec 113 ndash 146 sec

                                                                                                                                                                                      APTT 75 sec 25 ndash 34 sec

                                                                                                                                                                                      D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                                                                                      Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                                                                                      pH 728 738 to 742

                                                                                                                                                                                      PaO2 570 mmHg 80-100 mmHg

                                                                                                                                                                                      WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                      ALT 111 IUL 0ndash34 IUL

                                                                                                                                                                                      AST 61 IUL 0ndash34 IUL

                                                                                                                                                                                      BUN 303 mgdL 08-13 mgdL

                                                                                                                                                                                      Case Study 2 ndash Lab Results

                                                                                                                                                                                      Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                                                                                      Case Study 2 ndash Diagnosis

                                                                                                                                                                                      60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                                                                                      Case Study 3 ndash Presentation

                                                                                                                                                                                      TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                                                                      PT 228 sec 113 ndash 146 sec

                                                                                                                                                                                      APTT 45 sec 25 ndash 34 sec

                                                                                                                                                                                      D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                                                                      Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                                                                      FV Normal 70-120

                                                                                                                                                                                      FVII Normal 55-170

                                                                                                                                                                                      FVIII Normal 60-150

                                                                                                                                                                                      Protein C Normal 70-130

                                                                                                                                                                                      Hb 134 gdL 14-16 gdL

                                                                                                                                                                                      WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                      ALT 32 IUL 0ndash34 IUL

                                                                                                                                                                                      AST 28 IUL 0ndash34 IUL

                                                                                                                                                                                      BUN 09 mgdL 08-13 mgdL

                                                                                                                                                                                      Case Study 3 ndash Lab Results

                                                                                                                                                                                      Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                                                                      Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                                                                      Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                                                                      Case Study 4 ndash Presentation

                                                                                                                                                                                      TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                                                                      PT 28 sec 113 ndash 146 sec

                                                                                                                                                                                      APTT 71 sec 25 ndash 34 sec

                                                                                                                                                                                      D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                                                                      Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                                                                      FV Normal 70-120

                                                                                                                                                                                      FVII Normal 55-170

                                                                                                                                                                                      FVIII Normal 60-150

                                                                                                                                                                                      Protein C Normal 70-130

                                                                                                                                                                                      Hb 158 gdL 14-16 gdL

                                                                                                                                                                                      WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                      ALT 60 IUL 0ndash34 IUL

                                                                                                                                                                                      AST 47 IUL 0ndash34 IUL

                                                                                                                                                                                      BUN 38 mgdL 08-13 mgdL

                                                                                                                                                                                      Case Study 4 ndash Lab Results

                                                                                                                                                                                      Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                                                                      Case Study 4 ndash Diagnosis

                                                                                                                                                                                      55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                                                                      Case Study 5 ndash Presentation

                                                                                                                                                                                      Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                      Case Study 5 ndash Lab Results and Time Course

                                                                                                                                                                                      Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                      TEST RESULT REFERENCE RANGE

                                                                                                                                                                                      Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                                                                      PT 215 sec 103 ndash 128 sec

                                                                                                                                                                                      APTT 44 sec 26 ndash 36 sec

                                                                                                                                                                                      D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                                                                      Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                                                                      FII FV FVIII Low Not reported (NR)

                                                                                                                                                                                      FVII FIX FX vWF Normal NR

                                                                                                                                                                                      Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                                                                      DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                                                                      dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                                                                      (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                                                                      (D) Illustration demonstrating repair

                                                                                                                                                                                      Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                                                                      Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                      29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                                                      Case Study 6 ndash Presentation

                                                                                                                                                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                      Case Study 6 ndash Lab Results

                                                                                                                                                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                      TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                                                      PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                                                      INR 658 1 ndash 125

                                                                                                                                                                                      APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                                                      D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                                                      Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                                                      Albumin 28 gdL NR

                                                                                                                                                                                      Hb 58 gdL NR

                                                                                                                                                                                      LDH 1196 UL NR

                                                                                                                                                                                      SGPT 144 IU NR

                                                                                                                                                                                      SGOT 88 IU NR

                                                                                                                                                                                      Bilirubin 32 mgdL NR

                                                                                                                                                                                      DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                                                      day postop

                                                                                                                                                                                      Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                      HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                                                      Case Study 6 ndash Discussion

                                                                                                                                                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                      44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                                                      Case Study 7 ndash Presentation

                                                                                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                      On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                                                      Case Study 7 ndash Presentation

                                                                                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                      Case Study 7 ndash Lab Results vs Time

                                                                                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                      Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                                                      Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                      On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                                      Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                      DIC Take Home Messages

                                                                                                                                                                                      Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                                      Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                                      DIC

                                                                                                                                                                                      Thank you Questions

                                                                                                                                                                                      • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                                      • Learning Objectives
                                                                                                                                                                                      • Slide Number 3
                                                                                                                                                                                      • Slide Number 4
                                                                                                                                                                                      • Slide Number 5
                                                                                                                                                                                      • Slide Number 6
                                                                                                                                                                                      • Slide Number 7
                                                                                                                                                                                      • Slide Number 8
                                                                                                                                                                                      • Wound Sealing
                                                                                                                                                                                      • The Three Steps of Hemostasis
                                                                                                                                                                                      • Vessel Wall
                                                                                                                                                                                      • Slide Number 12
                                                                                                                                                                                      • Slide Number 13
                                                                                                                                                                                      • Platelet Structure UnactivatedActivated
                                                                                                                                                                                      • Primary Hemostasis
                                                                                                                                                                                      • Primary Hemostasis Assays
                                                                                                                                                                                      • Slide Number 17
                                                                                                                                                                                      • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                                      • Slide Number 19
                                                                                                                                                                                      • Coagulation factors
                                                                                                                                                                                      • Coagulation Assay Mechanisms
                                                                                                                                                                                      • Slide Number 22
                                                                                                                                                                                      • Fibrin Formation
                                                                                                                                                                                      • Slide Number 24
                                                                                                                                                                                      • Fibrinolysis Overview
                                                                                                                                                                                      • Fibrinolysis Overview
                                                                                                                                                                                      • Slide Number 27
                                                                                                                                                                                      • Fibrinolysis Releases D-dimers
                                                                                                                                                                                      • Basic Pathophysiology of DIC
                                                                                                                                                                                      • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                                      • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                                      • Clinical Conditions Associated With DIC
                                                                                                                                                                                      • Frequency of DIC in Selected Disease States
                                                                                                                                                                                      • Underlying Diseases in DIC Patients
                                                                                                                                                                                      • Slide Number 36
                                                                                                                                                                                      • Slide Number 37
                                                                                                                                                                                      • Slide Number 38
                                                                                                                                                                                      • Slide Number 39
                                                                                                                                                                                      • Pathophysiology of DIC
                                                                                                                                                                                      • Pathogenesis of DIC in Sepsis
                                                                                                                                                                                      • Host Response in Severe Sepsis
                                                                                                                                                                                      • Organ Failure in Severe Sepsis
                                                                                                                                                                                      • Mechanism of DIC in Organ Failure
                                                                                                                                                                                      • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                                      • Slide Number 47
                                                                                                                                                                                      • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                                      • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                                      • Mechanism of DIC
                                                                                                                                                                                      • Pathophysiology of DIC
                                                                                                                                                                                      • Pathophysiology of DIC - Mechanism
                                                                                                                                                                                      • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                                      • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                                      • Pathophysiology of Overt DIC
                                                                                                                                                                                      • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                                      • Slide Number 57
                                                                                                                                                                                      • Slide Number 58
                                                                                                                                                                                      • Slide Number 59
                                                                                                                                                                                      • Slide Number 60
                                                                                                                                                                                      • Slide Number 61
                                                                                                                                                                                      • BREAK
                                                                                                                                                                                      • Diagnostic and Management Approach for DIC
                                                                                                                                                                                      • Diagnosis of DIC
                                                                                                                                                                                      • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                                      • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                                      • Slide Number 67
                                                                                                                                                                                      • Slide Number 68
                                                                                                                                                                                      • British Journal of Haematology Overt DIC Score
                                                                                                                                                                                      • Slide Number 70
                                                                                                                                                                                      • Slide Number 71
                                                                                                                                                                                      • Slide Number 72
                                                                                                                                                                                      • Slide Number 73
                                                                                                                                                                                      • DIC Management Goals
                                                                                                                                                                                      • DIC Management and Treatment
                                                                                                                                                                                      • DIC Management Strategies
                                                                                                                                                                                      • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                                      • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                                      • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                                      • D-dimer FDPs and DIC
                                                                                                                                                                                      • D-Dimer and FDPs in DIC
                                                                                                                                                                                      • Follow Up of DIC State of Disease
                                                                                                                                                                                      • FMD-Dimer in DIC Major Differences
                                                                                                                                                                                      • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                                      • Slide Number 85
                                                                                                                                                                                      • Slide Number 86
                                                                                                                                                                                      • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                                      • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                      • Slide Number 94
                                                                                                                                                                                      • Slide Number 95
                                                                                                                                                                                      • Slide Number 96
                                                                                                                                                                                      • Slide Number 97
                                                                                                                                                                                      • Slide Number 98
                                                                                                                                                                                      • Slide Number 99
                                                                                                                                                                                      • DIC Case Studies
                                                                                                                                                                                      • Case Study 1 - Presentation
                                                                                                                                                                                      • Case Study 1 ndash Lab Results
                                                                                                                                                                                      • Case Study 1 ndash Microscopy
                                                                                                                                                                                      • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                                      • Slide Number 105
                                                                                                                                                                                      • Slide Number 106
                                                                                                                                                                                      • Slide Number 107
                                                                                                                                                                                      • Slide Number 108
                                                                                                                                                                                      • Slide Number 109
                                                                                                                                                                                      • Slide Number 110
                                                                                                                                                                                      • Slide Number 111
                                                                                                                                                                                      • Slide Number 112
                                                                                                                                                                                      • Slide Number 113
                                                                                                                                                                                      • Slide Number 114
                                                                                                                                                                                      • Slide Number 115
                                                                                                                                                                                      • Slide Number 116
                                                                                                                                                                                      • Slide Number 117
                                                                                                                                                                                      • Slide Number 118
                                                                                                                                                                                      • Slide Number 119
                                                                                                                                                                                      • Slide Number 120
                                                                                                                                                                                      • Slide Number 121
                                                                                                                                                                                      • Slide Number 122
                                                                                                                                                                                      • Slide Number 123
                                                                                                                                                                                      • Slide Number 124
                                                                                                                                                                                      • Slide Number 125
                                                                                                                                                                                      • DIC Take Home Messages
                                                                                                                                                                                      • Slide Number 127
                                                                                                                                                                                      • Slide Number 128

                                                                                                                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                                        In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC

                                                                                                                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                                        Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                                        Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                                        No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                                                                                                        Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                                                                                                        Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                                        Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                                        Non Overt DIC Overt DIC

                                                                                                                                                                                        AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                                                                                                        Trends in Markers of DIC for Different Patients

                                                                                                                                                                                        Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                                                                                                        Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                                                                                                        Trends in Markers of DIC for Different Patients

                                                                                                                                                                                        Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                                        FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                                                                                                        28 day outcome survival

                                                                                                                                                                                        28 day outcome death

                                                                                                                                                                                        Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                                                        Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                                                        Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                                                                                                        Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                                                        Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                                                        Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                                                                                                        DIC Case Studies

                                                                                                                                                                                        Case Study 1 - Presentation

                                                                                                                                                                                        18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                                                                                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                        Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                                                                                        WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                                                                                        RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                                                                                        Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                                                                                        Hematocrit 195 401 ndash 510

                                                                                                                                                                                        MCV 95 fL 790 ndash 922 fL

                                                                                                                                                                                        MPV 12 fL 94 ndash 124 fL

                                                                                                                                                                                        Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                                                                                        Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                                                                                        Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                                                                                        PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                                                                                        APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                                                                                        Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                                                                                        D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                                                                                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                        Case Study 1 ndash Microscopy

                                                                                                                                                                                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                        Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                                                                                        Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                                                                                        DIC due to TF release by APL blasts

                                                                                                                                                                                        Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                                                                                        Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                                                                                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                        20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                                                                                        Case Study 2 ndash Presentation

                                                                                                                                                                                        TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                                                                                        PT 30 sec 113 ndash 146 sec

                                                                                                                                                                                        APTT 75 sec 25 ndash 34 sec

                                                                                                                                                                                        D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                                                                                        Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                                                                                        pH 728 738 to 742

                                                                                                                                                                                        PaO2 570 mmHg 80-100 mmHg

                                                                                                                                                                                        WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                        ALT 111 IUL 0ndash34 IUL

                                                                                                                                                                                        AST 61 IUL 0ndash34 IUL

                                                                                                                                                                                        BUN 303 mgdL 08-13 mgdL

                                                                                                                                                                                        Case Study 2 ndash Lab Results

                                                                                                                                                                                        Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                                                                                        Case Study 2 ndash Diagnosis

                                                                                                                                                                                        60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                                                                                        Case Study 3 ndash Presentation

                                                                                                                                                                                        TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                                                                        PT 228 sec 113 ndash 146 sec

                                                                                                                                                                                        APTT 45 sec 25 ndash 34 sec

                                                                                                                                                                                        D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                                                                        Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                                                                        FV Normal 70-120

                                                                                                                                                                                        FVII Normal 55-170

                                                                                                                                                                                        FVIII Normal 60-150

                                                                                                                                                                                        Protein C Normal 70-130

                                                                                                                                                                                        Hb 134 gdL 14-16 gdL

                                                                                                                                                                                        WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                        ALT 32 IUL 0ndash34 IUL

                                                                                                                                                                                        AST 28 IUL 0ndash34 IUL

                                                                                                                                                                                        BUN 09 mgdL 08-13 mgdL

                                                                                                                                                                                        Case Study 3 ndash Lab Results

                                                                                                                                                                                        Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                                                                        Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                                                                        Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                                                                        Case Study 4 ndash Presentation

                                                                                                                                                                                        TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                                                                        PT 28 sec 113 ndash 146 sec

                                                                                                                                                                                        APTT 71 sec 25 ndash 34 sec

                                                                                                                                                                                        D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                                                                        Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                                                                        FV Normal 70-120

                                                                                                                                                                                        FVII Normal 55-170

                                                                                                                                                                                        FVIII Normal 60-150

                                                                                                                                                                                        Protein C Normal 70-130

                                                                                                                                                                                        Hb 158 gdL 14-16 gdL

                                                                                                                                                                                        WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                        ALT 60 IUL 0ndash34 IUL

                                                                                                                                                                                        AST 47 IUL 0ndash34 IUL

                                                                                                                                                                                        BUN 38 mgdL 08-13 mgdL

                                                                                                                                                                                        Case Study 4 ndash Lab Results

                                                                                                                                                                                        Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                                                                        Case Study 4 ndash Diagnosis

                                                                                                                                                                                        55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                                                                        Case Study 5 ndash Presentation

                                                                                                                                                                                        Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                        Case Study 5 ndash Lab Results and Time Course

                                                                                                                                                                                        Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                        TEST RESULT REFERENCE RANGE

                                                                                                                                                                                        Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                                                                        PT 215 sec 103 ndash 128 sec

                                                                                                                                                                                        APTT 44 sec 26 ndash 36 sec

                                                                                                                                                                                        D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                                                                        Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                                                                        FII FV FVIII Low Not reported (NR)

                                                                                                                                                                                        FVII FIX FX vWF Normal NR

                                                                                                                                                                                        Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                                                                        DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                                                                        dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                                                                        (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                                                                        (D) Illustration demonstrating repair

                                                                                                                                                                                        Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                                                                        Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                        29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                                                        Case Study 6 ndash Presentation

                                                                                                                                                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                        Case Study 6 ndash Lab Results

                                                                                                                                                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                        TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                                                        PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                                                        INR 658 1 ndash 125

                                                                                                                                                                                        APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                                                        D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                                                        Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                                                        Albumin 28 gdL NR

                                                                                                                                                                                        Hb 58 gdL NR

                                                                                                                                                                                        LDH 1196 UL NR

                                                                                                                                                                                        SGPT 144 IU NR

                                                                                                                                                                                        SGOT 88 IU NR

                                                                                                                                                                                        Bilirubin 32 mgdL NR

                                                                                                                                                                                        DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                                                        day postop

                                                                                                                                                                                        Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                        HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                                                        Case Study 6 ndash Discussion

                                                                                                                                                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                        44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                                                        Case Study 7 ndash Presentation

                                                                                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                        On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                                                        Case Study 7 ndash Presentation

                                                                                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                        Case Study 7 ndash Lab Results vs Time

                                                                                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                        Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                                                        Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                        On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                                        Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                        DIC Take Home Messages

                                                                                                                                                                                        Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                                        Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                                        DIC

                                                                                                                                                                                        Thank you Questions

                                                                                                                                                                                        • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                                        • Learning Objectives
                                                                                                                                                                                        • Slide Number 3
                                                                                                                                                                                        • Slide Number 4
                                                                                                                                                                                        • Slide Number 5
                                                                                                                                                                                        • Slide Number 6
                                                                                                                                                                                        • Slide Number 7
                                                                                                                                                                                        • Slide Number 8
                                                                                                                                                                                        • Wound Sealing
                                                                                                                                                                                        • The Three Steps of Hemostasis
                                                                                                                                                                                        • Vessel Wall
                                                                                                                                                                                        • Slide Number 12
                                                                                                                                                                                        • Slide Number 13
                                                                                                                                                                                        • Platelet Structure UnactivatedActivated
                                                                                                                                                                                        • Primary Hemostasis
                                                                                                                                                                                        • Primary Hemostasis Assays
                                                                                                                                                                                        • Slide Number 17
                                                                                                                                                                                        • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                                        • Slide Number 19
                                                                                                                                                                                        • Coagulation factors
                                                                                                                                                                                        • Coagulation Assay Mechanisms
                                                                                                                                                                                        • Slide Number 22
                                                                                                                                                                                        • Fibrin Formation
                                                                                                                                                                                        • Slide Number 24
                                                                                                                                                                                        • Fibrinolysis Overview
                                                                                                                                                                                        • Fibrinolysis Overview
                                                                                                                                                                                        • Slide Number 27
                                                                                                                                                                                        • Fibrinolysis Releases D-dimers
                                                                                                                                                                                        • Basic Pathophysiology of DIC
                                                                                                                                                                                        • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                                        • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                                        • Clinical Conditions Associated With DIC
                                                                                                                                                                                        • Frequency of DIC in Selected Disease States
                                                                                                                                                                                        • Underlying Diseases in DIC Patients
                                                                                                                                                                                        • Slide Number 36
                                                                                                                                                                                        • Slide Number 37
                                                                                                                                                                                        • Slide Number 38
                                                                                                                                                                                        • Slide Number 39
                                                                                                                                                                                        • Pathophysiology of DIC
                                                                                                                                                                                        • Pathogenesis of DIC in Sepsis
                                                                                                                                                                                        • Host Response in Severe Sepsis
                                                                                                                                                                                        • Organ Failure in Severe Sepsis
                                                                                                                                                                                        • Mechanism of DIC in Organ Failure
                                                                                                                                                                                        • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                                        • Slide Number 47
                                                                                                                                                                                        • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                                        • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                                        • Mechanism of DIC
                                                                                                                                                                                        • Pathophysiology of DIC
                                                                                                                                                                                        • Pathophysiology of DIC - Mechanism
                                                                                                                                                                                        • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                                        • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                                        • Pathophysiology of Overt DIC
                                                                                                                                                                                        • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                                        • Slide Number 57
                                                                                                                                                                                        • Slide Number 58
                                                                                                                                                                                        • Slide Number 59
                                                                                                                                                                                        • Slide Number 60
                                                                                                                                                                                        • Slide Number 61
                                                                                                                                                                                        • BREAK
                                                                                                                                                                                        • Diagnostic and Management Approach for DIC
                                                                                                                                                                                        • Diagnosis of DIC
                                                                                                                                                                                        • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                                        • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                                        • Slide Number 67
                                                                                                                                                                                        • Slide Number 68
                                                                                                                                                                                        • British Journal of Haematology Overt DIC Score
                                                                                                                                                                                        • Slide Number 70
                                                                                                                                                                                        • Slide Number 71
                                                                                                                                                                                        • Slide Number 72
                                                                                                                                                                                        • Slide Number 73
                                                                                                                                                                                        • DIC Management Goals
                                                                                                                                                                                        • DIC Management and Treatment
                                                                                                                                                                                        • DIC Management Strategies
                                                                                                                                                                                        • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                                        • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                                        • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                                        • D-dimer FDPs and DIC
                                                                                                                                                                                        • D-Dimer and FDPs in DIC
                                                                                                                                                                                        • Follow Up of DIC State of Disease
                                                                                                                                                                                        • FMD-Dimer in DIC Major Differences
                                                                                                                                                                                        • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                                        • Slide Number 85
                                                                                                                                                                                        • Slide Number 86
                                                                                                                                                                                        • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                                        • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                        • Slide Number 94
                                                                                                                                                                                        • Slide Number 95
                                                                                                                                                                                        • Slide Number 96
                                                                                                                                                                                        • Slide Number 97
                                                                                                                                                                                        • Slide Number 98
                                                                                                                                                                                        • Slide Number 99
                                                                                                                                                                                        • DIC Case Studies
                                                                                                                                                                                        • Case Study 1 - Presentation
                                                                                                                                                                                        • Case Study 1 ndash Lab Results
                                                                                                                                                                                        • Case Study 1 ndash Microscopy
                                                                                                                                                                                        • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                                        • Slide Number 105
                                                                                                                                                                                        • Slide Number 106
                                                                                                                                                                                        • Slide Number 107
                                                                                                                                                                                        • Slide Number 108
                                                                                                                                                                                        • Slide Number 109
                                                                                                                                                                                        • Slide Number 110
                                                                                                                                                                                        • Slide Number 111
                                                                                                                                                                                        • Slide Number 112
                                                                                                                                                                                        • Slide Number 113
                                                                                                                                                                                        • Slide Number 114
                                                                                                                                                                                        • Slide Number 115
                                                                                                                                                                                        • Slide Number 116
                                                                                                                                                                                        • Slide Number 117
                                                                                                                                                                                        • Slide Number 118
                                                                                                                                                                                        • Slide Number 119
                                                                                                                                                                                        • Slide Number 120
                                                                                                                                                                                        • Slide Number 121
                                                                                                                                                                                        • Slide Number 122
                                                                                                                                                                                        • Slide Number 123
                                                                                                                                                                                        • Slide Number 124
                                                                                                                                                                                        • Slide Number 125
                                                                                                                                                                                        • DIC Take Home Messages
                                                                                                                                                                                        • Slide Number 127
                                                                                                                                                                                        • Slide Number 128

                                                                                                                                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                                          Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6

                                                                                                                                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                                          Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                                          No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                                                                                                          Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                                                                                                          Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                                          Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                                          Non Overt DIC Overt DIC

                                                                                                                                                                                          AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                                                                                                          Trends in Markers of DIC for Different Patients

                                                                                                                                                                                          Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                                                                                                          Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                                                                                                          Trends in Markers of DIC for Different Patients

                                                                                                                                                                                          Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                                          FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                                                                                                          28 day outcome survival

                                                                                                                                                                                          28 day outcome death

                                                                                                                                                                                          Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                                                          Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                                                          Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                                                                                                          Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                                                          Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                                                          Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                                                                                                          DIC Case Studies

                                                                                                                                                                                          Case Study 1 - Presentation

                                                                                                                                                                                          18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                                                                                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                          Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                                                                                          WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                                                                                          RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                                                                                          Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                                                                                          Hematocrit 195 401 ndash 510

                                                                                                                                                                                          MCV 95 fL 790 ndash 922 fL

                                                                                                                                                                                          MPV 12 fL 94 ndash 124 fL

                                                                                                                                                                                          Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                                                                                          Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                                                                                          Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                                                                                          PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                                                                                          APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                                                                                          Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                                                                                          D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                                                                                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                          Case Study 1 ndash Microscopy

                                                                                                                                                                                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                          Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                                                                                          Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                                                                                          DIC due to TF release by APL blasts

                                                                                                                                                                                          Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                                                                                          Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                                                                                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                          20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                                                                                          Case Study 2 ndash Presentation

                                                                                                                                                                                          TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                                                                                          PT 30 sec 113 ndash 146 sec

                                                                                                                                                                                          APTT 75 sec 25 ndash 34 sec

                                                                                                                                                                                          D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                                                                                          Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                                                                                          pH 728 738 to 742

                                                                                                                                                                                          PaO2 570 mmHg 80-100 mmHg

                                                                                                                                                                                          WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                          ALT 111 IUL 0ndash34 IUL

                                                                                                                                                                                          AST 61 IUL 0ndash34 IUL

                                                                                                                                                                                          BUN 303 mgdL 08-13 mgdL

                                                                                                                                                                                          Case Study 2 ndash Lab Results

                                                                                                                                                                                          Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                                                                                          Case Study 2 ndash Diagnosis

                                                                                                                                                                                          60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                                                                                          Case Study 3 ndash Presentation

                                                                                                                                                                                          TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                                                                          PT 228 sec 113 ndash 146 sec

                                                                                                                                                                                          APTT 45 sec 25 ndash 34 sec

                                                                                                                                                                                          D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                                                                          Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                                                                          FV Normal 70-120

                                                                                                                                                                                          FVII Normal 55-170

                                                                                                                                                                                          FVIII Normal 60-150

                                                                                                                                                                                          Protein C Normal 70-130

                                                                                                                                                                                          Hb 134 gdL 14-16 gdL

                                                                                                                                                                                          WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                          ALT 32 IUL 0ndash34 IUL

                                                                                                                                                                                          AST 28 IUL 0ndash34 IUL

                                                                                                                                                                                          BUN 09 mgdL 08-13 mgdL

                                                                                                                                                                                          Case Study 3 ndash Lab Results

                                                                                                                                                                                          Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                                                                          Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                                                                          Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                                                                          Case Study 4 ndash Presentation

                                                                                                                                                                                          TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                                                                          PT 28 sec 113 ndash 146 sec

                                                                                                                                                                                          APTT 71 sec 25 ndash 34 sec

                                                                                                                                                                                          D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                                                                          Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                                                                          FV Normal 70-120

                                                                                                                                                                                          FVII Normal 55-170

                                                                                                                                                                                          FVIII Normal 60-150

                                                                                                                                                                                          Protein C Normal 70-130

                                                                                                                                                                                          Hb 158 gdL 14-16 gdL

                                                                                                                                                                                          WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                          ALT 60 IUL 0ndash34 IUL

                                                                                                                                                                                          AST 47 IUL 0ndash34 IUL

                                                                                                                                                                                          BUN 38 mgdL 08-13 mgdL

                                                                                                                                                                                          Case Study 4 ndash Lab Results

                                                                                                                                                                                          Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                                                                          Case Study 4 ndash Diagnosis

                                                                                                                                                                                          55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                                                                          Case Study 5 ndash Presentation

                                                                                                                                                                                          Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                          Case Study 5 ndash Lab Results and Time Course

                                                                                                                                                                                          Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                          TEST RESULT REFERENCE RANGE

                                                                                                                                                                                          Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                                                                          PT 215 sec 103 ndash 128 sec

                                                                                                                                                                                          APTT 44 sec 26 ndash 36 sec

                                                                                                                                                                                          D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                                                                          Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                                                                          FII FV FVIII Low Not reported (NR)

                                                                                                                                                                                          FVII FIX FX vWF Normal NR

                                                                                                                                                                                          Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                                                                          DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                                                                          dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                                                                          (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                                                                          (D) Illustration demonstrating repair

                                                                                                                                                                                          Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                                                                          Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                          29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                                                          Case Study 6 ndash Presentation

                                                                                                                                                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                          Case Study 6 ndash Lab Results

                                                                                                                                                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                          TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                                                          PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                                                          INR 658 1 ndash 125

                                                                                                                                                                                          APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                                                          D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                                                          Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                                                          Albumin 28 gdL NR

                                                                                                                                                                                          Hb 58 gdL NR

                                                                                                                                                                                          LDH 1196 UL NR

                                                                                                                                                                                          SGPT 144 IU NR

                                                                                                                                                                                          SGOT 88 IU NR

                                                                                                                                                                                          Bilirubin 32 mgdL NR

                                                                                                                                                                                          DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                                                          day postop

                                                                                                                                                                                          Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                          HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                                                          Case Study 6 ndash Discussion

                                                                                                                                                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                          44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                                                          Case Study 7 ndash Presentation

                                                                                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                          On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                                                          Case Study 7 ndash Presentation

                                                                                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                          Case Study 7 ndash Lab Results vs Time

                                                                                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                          Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                                                          Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                          On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                                          Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                          DIC Take Home Messages

                                                                                                                                                                                          Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                                          Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                                          DIC

                                                                                                                                                                                          Thank you Questions

                                                                                                                                                                                          • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                                          • Learning Objectives
                                                                                                                                                                                          • Slide Number 3
                                                                                                                                                                                          • Slide Number 4
                                                                                                                                                                                          • Slide Number 5
                                                                                                                                                                                          • Slide Number 6
                                                                                                                                                                                          • Slide Number 7
                                                                                                                                                                                          • Slide Number 8
                                                                                                                                                                                          • Wound Sealing
                                                                                                                                                                                          • The Three Steps of Hemostasis
                                                                                                                                                                                          • Vessel Wall
                                                                                                                                                                                          • Slide Number 12
                                                                                                                                                                                          • Slide Number 13
                                                                                                                                                                                          • Platelet Structure UnactivatedActivated
                                                                                                                                                                                          • Primary Hemostasis
                                                                                                                                                                                          • Primary Hemostasis Assays
                                                                                                                                                                                          • Slide Number 17
                                                                                                                                                                                          • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                                          • Slide Number 19
                                                                                                                                                                                          • Coagulation factors
                                                                                                                                                                                          • Coagulation Assay Mechanisms
                                                                                                                                                                                          • Slide Number 22
                                                                                                                                                                                          • Fibrin Formation
                                                                                                                                                                                          • Slide Number 24
                                                                                                                                                                                          • Fibrinolysis Overview
                                                                                                                                                                                          • Fibrinolysis Overview
                                                                                                                                                                                          • Slide Number 27
                                                                                                                                                                                          • Fibrinolysis Releases D-dimers
                                                                                                                                                                                          • Basic Pathophysiology of DIC
                                                                                                                                                                                          • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                                          • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                                          • Clinical Conditions Associated With DIC
                                                                                                                                                                                          • Frequency of DIC in Selected Disease States
                                                                                                                                                                                          • Underlying Diseases in DIC Patients
                                                                                                                                                                                          • Slide Number 36
                                                                                                                                                                                          • Slide Number 37
                                                                                                                                                                                          • Slide Number 38
                                                                                                                                                                                          • Slide Number 39
                                                                                                                                                                                          • Pathophysiology of DIC
                                                                                                                                                                                          • Pathogenesis of DIC in Sepsis
                                                                                                                                                                                          • Host Response in Severe Sepsis
                                                                                                                                                                                          • Organ Failure in Severe Sepsis
                                                                                                                                                                                          • Mechanism of DIC in Organ Failure
                                                                                                                                                                                          • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                                          • Slide Number 47
                                                                                                                                                                                          • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                                          • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                                          • Mechanism of DIC
                                                                                                                                                                                          • Pathophysiology of DIC
                                                                                                                                                                                          • Pathophysiology of DIC - Mechanism
                                                                                                                                                                                          • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                                          • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                                          • Pathophysiology of Overt DIC
                                                                                                                                                                                          • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                                          • Slide Number 57
                                                                                                                                                                                          • Slide Number 58
                                                                                                                                                                                          • Slide Number 59
                                                                                                                                                                                          • Slide Number 60
                                                                                                                                                                                          • Slide Number 61
                                                                                                                                                                                          • BREAK
                                                                                                                                                                                          • Diagnostic and Management Approach for DIC
                                                                                                                                                                                          • Diagnosis of DIC
                                                                                                                                                                                          • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                                          • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                                          • Slide Number 67
                                                                                                                                                                                          • Slide Number 68
                                                                                                                                                                                          • British Journal of Haematology Overt DIC Score
                                                                                                                                                                                          • Slide Number 70
                                                                                                                                                                                          • Slide Number 71
                                                                                                                                                                                          • Slide Number 72
                                                                                                                                                                                          • Slide Number 73
                                                                                                                                                                                          • DIC Management Goals
                                                                                                                                                                                          • DIC Management and Treatment
                                                                                                                                                                                          • DIC Management Strategies
                                                                                                                                                                                          • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                                          • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                                          • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                                          • D-dimer FDPs and DIC
                                                                                                                                                                                          • D-Dimer and FDPs in DIC
                                                                                                                                                                                          • Follow Up of DIC State of Disease
                                                                                                                                                                                          • FMD-Dimer in DIC Major Differences
                                                                                                                                                                                          • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                                          • Slide Number 85
                                                                                                                                                                                          • Slide Number 86
                                                                                                                                                                                          • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                                          • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                          • Slide Number 94
                                                                                                                                                                                          • Slide Number 95
                                                                                                                                                                                          • Slide Number 96
                                                                                                                                                                                          • Slide Number 97
                                                                                                                                                                                          • Slide Number 98
                                                                                                                                                                                          • Slide Number 99
                                                                                                                                                                                          • DIC Case Studies
                                                                                                                                                                                          • Case Study 1 - Presentation
                                                                                                                                                                                          • Case Study 1 ndash Lab Results
                                                                                                                                                                                          • Case Study 1 ndash Microscopy
                                                                                                                                                                                          • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                                          • Slide Number 105
                                                                                                                                                                                          • Slide Number 106
                                                                                                                                                                                          • Slide Number 107
                                                                                                                                                                                          • Slide Number 108
                                                                                                                                                                                          • Slide Number 109
                                                                                                                                                                                          • Slide Number 110
                                                                                                                                                                                          • Slide Number 111
                                                                                                                                                                                          • Slide Number 112
                                                                                                                                                                                          • Slide Number 113
                                                                                                                                                                                          • Slide Number 114
                                                                                                                                                                                          • Slide Number 115
                                                                                                                                                                                          • Slide Number 116
                                                                                                                                                                                          • Slide Number 117
                                                                                                                                                                                          • Slide Number 118
                                                                                                                                                                                          • Slide Number 119
                                                                                                                                                                                          • Slide Number 120
                                                                                                                                                                                          • Slide Number 121
                                                                                                                                                                                          • Slide Number 122
                                                                                                                                                                                          • Slide Number 123
                                                                                                                                                                                          • Slide Number 124
                                                                                                                                                                                          • Slide Number 125
                                                                                                                                                                                          • DIC Take Home Messages
                                                                                                                                                                                          • Slide Number 127
                                                                                                                                                                                          • Slide Number 128

                                                                                                                                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                                            Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                                            No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC

                                                                                                                                                                                            Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC

                                                                                                                                                                                            Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                                            Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                                            Non Overt DIC Overt DIC

                                                                                                                                                                                            AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                                                                                                            Trends in Markers of DIC for Different Patients

                                                                                                                                                                                            Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                                                                                                            Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                                                                                                            Trends in Markers of DIC for Different Patients

                                                                                                                                                                                            Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                                            FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                                                                                                            28 day outcome survival

                                                                                                                                                                                            28 day outcome death

                                                                                                                                                                                            Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                                                            Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                                                            Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                                                                                                            Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                                                            Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                                                            Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                                                                                                            DIC Case Studies

                                                                                                                                                                                            Case Study 1 - Presentation

                                                                                                                                                                                            18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                                                                                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                            Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                                                                                            WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                                                                                            RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                                                                                            Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                                                                                            Hematocrit 195 401 ndash 510

                                                                                                                                                                                            MCV 95 fL 790 ndash 922 fL

                                                                                                                                                                                            MPV 12 fL 94 ndash 124 fL

                                                                                                                                                                                            Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                                                                                            Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                                                                                            Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                                                                                            PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                                                                                            APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                                                                                            Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                                                                                            D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                                                                                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                            Case Study 1 ndash Microscopy

                                                                                                                                                                                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                            Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                                                                                            Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                                                                                            DIC due to TF release by APL blasts

                                                                                                                                                                                            Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                                                                                            Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                                                                                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                            20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                                                                                            Case Study 2 ndash Presentation

                                                                                                                                                                                            TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                                                                                            PT 30 sec 113 ndash 146 sec

                                                                                                                                                                                            APTT 75 sec 25 ndash 34 sec

                                                                                                                                                                                            D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                                                                                            Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                                                                                            pH 728 738 to 742

                                                                                                                                                                                            PaO2 570 mmHg 80-100 mmHg

                                                                                                                                                                                            WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                            ALT 111 IUL 0ndash34 IUL

                                                                                                                                                                                            AST 61 IUL 0ndash34 IUL

                                                                                                                                                                                            BUN 303 mgdL 08-13 mgdL

                                                                                                                                                                                            Case Study 2 ndash Lab Results

                                                                                                                                                                                            Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                                                                                            Case Study 2 ndash Diagnosis

                                                                                                                                                                                            60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                                                                                            Case Study 3 ndash Presentation

                                                                                                                                                                                            TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                                                                            PT 228 sec 113 ndash 146 sec

                                                                                                                                                                                            APTT 45 sec 25 ndash 34 sec

                                                                                                                                                                                            D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                                                                            Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                                                                            FV Normal 70-120

                                                                                                                                                                                            FVII Normal 55-170

                                                                                                                                                                                            FVIII Normal 60-150

                                                                                                                                                                                            Protein C Normal 70-130

                                                                                                                                                                                            Hb 134 gdL 14-16 gdL

                                                                                                                                                                                            WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                            ALT 32 IUL 0ndash34 IUL

                                                                                                                                                                                            AST 28 IUL 0ndash34 IUL

                                                                                                                                                                                            BUN 09 mgdL 08-13 mgdL

                                                                                                                                                                                            Case Study 3 ndash Lab Results

                                                                                                                                                                                            Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                                                                            Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                                                                            Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                                                                            Case Study 4 ndash Presentation

                                                                                                                                                                                            TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                                                                            PT 28 sec 113 ndash 146 sec

                                                                                                                                                                                            APTT 71 sec 25 ndash 34 sec

                                                                                                                                                                                            D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                                                                            Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                                                                            FV Normal 70-120

                                                                                                                                                                                            FVII Normal 55-170

                                                                                                                                                                                            FVIII Normal 60-150

                                                                                                                                                                                            Protein C Normal 70-130

                                                                                                                                                                                            Hb 158 gdL 14-16 gdL

                                                                                                                                                                                            WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                            ALT 60 IUL 0ndash34 IUL

                                                                                                                                                                                            AST 47 IUL 0ndash34 IUL

                                                                                                                                                                                            BUN 38 mgdL 08-13 mgdL

                                                                                                                                                                                            Case Study 4 ndash Lab Results

                                                                                                                                                                                            Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                                                                            Case Study 4 ndash Diagnosis

                                                                                                                                                                                            55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                                                                            Case Study 5 ndash Presentation

                                                                                                                                                                                            Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                            Case Study 5 ndash Lab Results and Time Course

                                                                                                                                                                                            Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                            TEST RESULT REFERENCE RANGE

                                                                                                                                                                                            Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                                                                            PT 215 sec 103 ndash 128 sec

                                                                                                                                                                                            APTT 44 sec 26 ndash 36 sec

                                                                                                                                                                                            D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                                                                            Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                                                                            FII FV FVIII Low Not reported (NR)

                                                                                                                                                                                            FVII FIX FX vWF Normal NR

                                                                                                                                                                                            Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                                                                            DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                                                                            dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                                                                            (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                                                                            (D) Illustration demonstrating repair

                                                                                                                                                                                            Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                                                                            Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                            29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                                                            Case Study 6 ndash Presentation

                                                                                                                                                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                            Case Study 6 ndash Lab Results

                                                                                                                                                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                            TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                                                            PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                                                            INR 658 1 ndash 125

                                                                                                                                                                                            APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                                                            D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                                                            Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                                                            Albumin 28 gdL NR

                                                                                                                                                                                            Hb 58 gdL NR

                                                                                                                                                                                            LDH 1196 UL NR

                                                                                                                                                                                            SGPT 144 IU NR

                                                                                                                                                                                            SGOT 88 IU NR

                                                                                                                                                                                            Bilirubin 32 mgdL NR

                                                                                                                                                                                            DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                                                            day postop

                                                                                                                                                                                            Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                            HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                                                            Case Study 6 ndash Discussion

                                                                                                                                                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                            44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                                                            Case Study 7 ndash Presentation

                                                                                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                            On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                                                            Case Study 7 ndash Presentation

                                                                                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                            Case Study 7 ndash Lab Results vs Time

                                                                                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                            Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                                                            Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                            On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                                            Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                            DIC Take Home Messages

                                                                                                                                                                                            Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                                            Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                                            DIC

                                                                                                                                                                                            Thank you Questions

                                                                                                                                                                                            • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                                            • Learning Objectives
                                                                                                                                                                                            • Slide Number 3
                                                                                                                                                                                            • Slide Number 4
                                                                                                                                                                                            • Slide Number 5
                                                                                                                                                                                            • Slide Number 6
                                                                                                                                                                                            • Slide Number 7
                                                                                                                                                                                            • Slide Number 8
                                                                                                                                                                                            • Wound Sealing
                                                                                                                                                                                            • The Three Steps of Hemostasis
                                                                                                                                                                                            • Vessel Wall
                                                                                                                                                                                            • Slide Number 12
                                                                                                                                                                                            • Slide Number 13
                                                                                                                                                                                            • Platelet Structure UnactivatedActivated
                                                                                                                                                                                            • Primary Hemostasis
                                                                                                                                                                                            • Primary Hemostasis Assays
                                                                                                                                                                                            • Slide Number 17
                                                                                                                                                                                            • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                                            • Slide Number 19
                                                                                                                                                                                            • Coagulation factors
                                                                                                                                                                                            • Coagulation Assay Mechanisms
                                                                                                                                                                                            • Slide Number 22
                                                                                                                                                                                            • Fibrin Formation
                                                                                                                                                                                            • Slide Number 24
                                                                                                                                                                                            • Fibrinolysis Overview
                                                                                                                                                                                            • Fibrinolysis Overview
                                                                                                                                                                                            • Slide Number 27
                                                                                                                                                                                            • Fibrinolysis Releases D-dimers
                                                                                                                                                                                            • Basic Pathophysiology of DIC
                                                                                                                                                                                            • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                                            • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                                            • Clinical Conditions Associated With DIC
                                                                                                                                                                                            • Frequency of DIC in Selected Disease States
                                                                                                                                                                                            • Underlying Diseases in DIC Patients
                                                                                                                                                                                            • Slide Number 36
                                                                                                                                                                                            • Slide Number 37
                                                                                                                                                                                            • Slide Number 38
                                                                                                                                                                                            • Slide Number 39
                                                                                                                                                                                            • Pathophysiology of DIC
                                                                                                                                                                                            • Pathogenesis of DIC in Sepsis
                                                                                                                                                                                            • Host Response in Severe Sepsis
                                                                                                                                                                                            • Organ Failure in Severe Sepsis
                                                                                                                                                                                            • Mechanism of DIC in Organ Failure
                                                                                                                                                                                            • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                                            • Slide Number 47
                                                                                                                                                                                            • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                                            • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                                            • Mechanism of DIC
                                                                                                                                                                                            • Pathophysiology of DIC
                                                                                                                                                                                            • Pathophysiology of DIC - Mechanism
                                                                                                                                                                                            • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                                            • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                                            • Pathophysiology of Overt DIC
                                                                                                                                                                                            • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                                            • Slide Number 57
                                                                                                                                                                                            • Slide Number 58
                                                                                                                                                                                            • Slide Number 59
                                                                                                                                                                                            • Slide Number 60
                                                                                                                                                                                            • Slide Number 61
                                                                                                                                                                                            • BREAK
                                                                                                                                                                                            • Diagnostic and Management Approach for DIC
                                                                                                                                                                                            • Diagnosis of DIC
                                                                                                                                                                                            • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                                            • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                                            • Slide Number 67
                                                                                                                                                                                            • Slide Number 68
                                                                                                                                                                                            • British Journal of Haematology Overt DIC Score
                                                                                                                                                                                            • Slide Number 70
                                                                                                                                                                                            • Slide Number 71
                                                                                                                                                                                            • Slide Number 72
                                                                                                                                                                                            • Slide Number 73
                                                                                                                                                                                            • DIC Management Goals
                                                                                                                                                                                            • DIC Management and Treatment
                                                                                                                                                                                            • DIC Management Strategies
                                                                                                                                                                                            • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                                            • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                                            • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                                            • D-dimer FDPs and DIC
                                                                                                                                                                                            • D-Dimer and FDPs in DIC
                                                                                                                                                                                            • Follow Up of DIC State of Disease
                                                                                                                                                                                            • FMD-Dimer in DIC Major Differences
                                                                                                                                                                                            • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                                            • Slide Number 85
                                                                                                                                                                                            • Slide Number 86
                                                                                                                                                                                            • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                                            • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                            • Slide Number 94
                                                                                                                                                                                            • Slide Number 95
                                                                                                                                                                                            • Slide Number 96
                                                                                                                                                                                            • Slide Number 97
                                                                                                                                                                                            • Slide Number 98
                                                                                                                                                                                            • Slide Number 99
                                                                                                                                                                                            • DIC Case Studies
                                                                                                                                                                                            • Case Study 1 - Presentation
                                                                                                                                                                                            • Case Study 1 ndash Lab Results
                                                                                                                                                                                            • Case Study 1 ndash Microscopy
                                                                                                                                                                                            • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                                            • Slide Number 105
                                                                                                                                                                                            • Slide Number 106
                                                                                                                                                                                            • Slide Number 107
                                                                                                                                                                                            • Slide Number 108
                                                                                                                                                                                            • Slide Number 109
                                                                                                                                                                                            • Slide Number 110
                                                                                                                                                                                            • Slide Number 111
                                                                                                                                                                                            • Slide Number 112
                                                                                                                                                                                            • Slide Number 113
                                                                                                                                                                                            • Slide Number 114
                                                                                                                                                                                            • Slide Number 115
                                                                                                                                                                                            • Slide Number 116
                                                                                                                                                                                            • Slide Number 117
                                                                                                                                                                                            • Slide Number 118
                                                                                                                                                                                            • Slide Number 119
                                                                                                                                                                                            • Slide Number 120
                                                                                                                                                                                            • Slide Number 121
                                                                                                                                                                                            • Slide Number 122
                                                                                                                                                                                            • Slide Number 123
                                                                                                                                                                                            • Slide Number 124
                                                                                                                                                                                            • Slide Number 125
                                                                                                                                                                                            • DIC Take Home Messages
                                                                                                                                                                                            • Slide Number 127
                                                                                                                                                                                            • Slide Number 128

                                                                                                                                                                                              Diagnostic Performance of FM and D-dimer in DIC

                                                                                                                                                                                              Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                                              Non Overt DIC Overt DIC

                                                                                                                                                                                              AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC

                                                                                                                                                                                              Trends in Markers of DIC for Different Patients

                                                                                                                                                                                              Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                                                                                                              Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                                                                                                              Trends in Markers of DIC for Different Patients

                                                                                                                                                                                              Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                                              FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                                                                                                              28 day outcome survival

                                                                                                                                                                                              28 day outcome death

                                                                                                                                                                                              Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                                                              Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                                                              Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                                                                                                              Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                                                              Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                                                              Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                                                                                                              DIC Case Studies

                                                                                                                                                                                              Case Study 1 - Presentation

                                                                                                                                                                                              18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                                                                                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                              Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                                                                                              WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                                                                                              RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                                                                                              Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                                                                                              Hematocrit 195 401 ndash 510

                                                                                                                                                                                              MCV 95 fL 790 ndash 922 fL

                                                                                                                                                                                              MPV 12 fL 94 ndash 124 fL

                                                                                                                                                                                              Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                                                                                              Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                                                                                              Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                                                                                              PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                                                                                              APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                                                                                              Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                                                                                              D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                                                                                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                              Case Study 1 ndash Microscopy

                                                                                                                                                                                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                              Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                                                                                              Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                                                                                              DIC due to TF release by APL blasts

                                                                                                                                                                                              Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                                                                                              Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                                                                                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                              20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                                                                                              Case Study 2 ndash Presentation

                                                                                                                                                                                              TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                                                                                              PT 30 sec 113 ndash 146 sec

                                                                                                                                                                                              APTT 75 sec 25 ndash 34 sec

                                                                                                                                                                                              D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                                                                                              Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                                                                                              pH 728 738 to 742

                                                                                                                                                                                              PaO2 570 mmHg 80-100 mmHg

                                                                                                                                                                                              WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                              ALT 111 IUL 0ndash34 IUL

                                                                                                                                                                                              AST 61 IUL 0ndash34 IUL

                                                                                                                                                                                              BUN 303 mgdL 08-13 mgdL

                                                                                                                                                                                              Case Study 2 ndash Lab Results

                                                                                                                                                                                              Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                                                                                              Case Study 2 ndash Diagnosis

                                                                                                                                                                                              60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                                                                                              Case Study 3 ndash Presentation

                                                                                                                                                                                              TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                                                                              PT 228 sec 113 ndash 146 sec

                                                                                                                                                                                              APTT 45 sec 25 ndash 34 sec

                                                                                                                                                                                              D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                                                                              Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                                                                              FV Normal 70-120

                                                                                                                                                                                              FVII Normal 55-170

                                                                                                                                                                                              FVIII Normal 60-150

                                                                                                                                                                                              Protein C Normal 70-130

                                                                                                                                                                                              Hb 134 gdL 14-16 gdL

                                                                                                                                                                                              WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                              ALT 32 IUL 0ndash34 IUL

                                                                                                                                                                                              AST 28 IUL 0ndash34 IUL

                                                                                                                                                                                              BUN 09 mgdL 08-13 mgdL

                                                                                                                                                                                              Case Study 3 ndash Lab Results

                                                                                                                                                                                              Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                                                                              Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                                                                              Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                                                                              Case Study 4 ndash Presentation

                                                                                                                                                                                              TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                                                                              PT 28 sec 113 ndash 146 sec

                                                                                                                                                                                              APTT 71 sec 25 ndash 34 sec

                                                                                                                                                                                              D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                                                                              Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                                                                              FV Normal 70-120

                                                                                                                                                                                              FVII Normal 55-170

                                                                                                                                                                                              FVIII Normal 60-150

                                                                                                                                                                                              Protein C Normal 70-130

                                                                                                                                                                                              Hb 158 gdL 14-16 gdL

                                                                                                                                                                                              WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                              ALT 60 IUL 0ndash34 IUL

                                                                                                                                                                                              AST 47 IUL 0ndash34 IUL

                                                                                                                                                                                              BUN 38 mgdL 08-13 mgdL

                                                                                                                                                                                              Case Study 4 ndash Lab Results

                                                                                                                                                                                              Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                                                                              Case Study 4 ndash Diagnosis

                                                                                                                                                                                              55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                                                                              Case Study 5 ndash Presentation

                                                                                                                                                                                              Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                              Case Study 5 ndash Lab Results and Time Course

                                                                                                                                                                                              Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                              TEST RESULT REFERENCE RANGE

                                                                                                                                                                                              Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                                                                              PT 215 sec 103 ndash 128 sec

                                                                                                                                                                                              APTT 44 sec 26 ndash 36 sec

                                                                                                                                                                                              D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                                                                              Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                                                                              FII FV FVIII Low Not reported (NR)

                                                                                                                                                                                              FVII FIX FX vWF Normal NR

                                                                                                                                                                                              Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                                                                              DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                                                                              dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                                                                              (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                                                                              (D) Illustration demonstrating repair

                                                                                                                                                                                              Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                                                                              Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                              29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                                                              Case Study 6 ndash Presentation

                                                                                                                                                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                              Case Study 6 ndash Lab Results

                                                                                                                                                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                              TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                                                              PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                                                              INR 658 1 ndash 125

                                                                                                                                                                                              APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                                                              D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                                                              Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                                                              Albumin 28 gdL NR

                                                                                                                                                                                              Hb 58 gdL NR

                                                                                                                                                                                              LDH 1196 UL NR

                                                                                                                                                                                              SGPT 144 IU NR

                                                                                                                                                                                              SGOT 88 IU NR

                                                                                                                                                                                              Bilirubin 32 mgdL NR

                                                                                                                                                                                              DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                                                              day postop

                                                                                                                                                                                              Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                              HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                                                              Case Study 6 ndash Discussion

                                                                                                                                                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                              44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                                                              Case Study 7 ndash Presentation

                                                                                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                              On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                                                              Case Study 7 ndash Presentation

                                                                                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                              Case Study 7 ndash Lab Results vs Time

                                                                                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                              Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                                                              Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                              On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                                              Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                              DIC Take Home Messages

                                                                                                                                                                                              Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                                              Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                                              DIC

                                                                                                                                                                                              Thank you Questions

                                                                                                                                                                                              • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                                              • Learning Objectives
                                                                                                                                                                                              • Slide Number 3
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                                                                                                                                                                                              • Slide Number 8
                                                                                                                                                                                              • Wound Sealing
                                                                                                                                                                                              • The Three Steps of Hemostasis
                                                                                                                                                                                              • Vessel Wall
                                                                                                                                                                                              • Slide Number 12
                                                                                                                                                                                              • Slide Number 13
                                                                                                                                                                                              • Platelet Structure UnactivatedActivated
                                                                                                                                                                                              • Primary Hemostasis
                                                                                                                                                                                              • Primary Hemostasis Assays
                                                                                                                                                                                              • Slide Number 17
                                                                                                                                                                                              • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                                              • Slide Number 19
                                                                                                                                                                                              • Coagulation factors
                                                                                                                                                                                              • Coagulation Assay Mechanisms
                                                                                                                                                                                              • Slide Number 22
                                                                                                                                                                                              • Fibrin Formation
                                                                                                                                                                                              • Slide Number 24
                                                                                                                                                                                              • Fibrinolysis Overview
                                                                                                                                                                                              • Fibrinolysis Overview
                                                                                                                                                                                              • Slide Number 27
                                                                                                                                                                                              • Fibrinolysis Releases D-dimers
                                                                                                                                                                                              • Basic Pathophysiology of DIC
                                                                                                                                                                                              • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                                              • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                                              • Clinical Conditions Associated With DIC
                                                                                                                                                                                              • Frequency of DIC in Selected Disease States
                                                                                                                                                                                              • Underlying Diseases in DIC Patients
                                                                                                                                                                                              • Slide Number 36
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                                                                                                                                                                                              • Slide Number 39
                                                                                                                                                                                              • Pathophysiology of DIC
                                                                                                                                                                                              • Pathogenesis of DIC in Sepsis
                                                                                                                                                                                              • Host Response in Severe Sepsis
                                                                                                                                                                                              • Organ Failure in Severe Sepsis
                                                                                                                                                                                              • Mechanism of DIC in Organ Failure
                                                                                                                                                                                              • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                                              • Slide Number 47
                                                                                                                                                                                              • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                                              • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                                              • Mechanism of DIC
                                                                                                                                                                                              • Pathophysiology of DIC
                                                                                                                                                                                              • Pathophysiology of DIC - Mechanism
                                                                                                                                                                                              • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                                              • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                                              • Pathophysiology of Overt DIC
                                                                                                                                                                                              • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                                              • Slide Number 57
                                                                                                                                                                                              • Slide Number 58
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                                                                                                                                                                                              • Slide Number 60
                                                                                                                                                                                              • Slide Number 61
                                                                                                                                                                                              • BREAK
                                                                                                                                                                                              • Diagnostic and Management Approach for DIC
                                                                                                                                                                                              • Diagnosis of DIC
                                                                                                                                                                                              • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                                              • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                                              • Slide Number 67
                                                                                                                                                                                              • Slide Number 68
                                                                                                                                                                                              • British Journal of Haematology Overt DIC Score
                                                                                                                                                                                              • Slide Number 70
                                                                                                                                                                                              • Slide Number 71
                                                                                                                                                                                              • Slide Number 72
                                                                                                                                                                                              • Slide Number 73
                                                                                                                                                                                              • DIC Management Goals
                                                                                                                                                                                              • DIC Management and Treatment
                                                                                                                                                                                              • DIC Management Strategies
                                                                                                                                                                                              • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                                              • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                                              • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                                              • D-dimer FDPs and DIC
                                                                                                                                                                                              • D-Dimer and FDPs in DIC
                                                                                                                                                                                              • Follow Up of DIC State of Disease
                                                                                                                                                                                              • FMD-Dimer in DIC Major Differences
                                                                                                                                                                                              • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                                              • Slide Number 85
                                                                                                                                                                                              • Slide Number 86
                                                                                                                                                                                              • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                                              • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                              • Slide Number 94
                                                                                                                                                                                              • Slide Number 95
                                                                                                                                                                                              • Slide Number 96
                                                                                                                                                                                              • Slide Number 97
                                                                                                                                                                                              • Slide Number 98
                                                                                                                                                                                              • Slide Number 99
                                                                                                                                                                                              • DIC Case Studies
                                                                                                                                                                                              • Case Study 1 - Presentation
                                                                                                                                                                                              • Case Study 1 ndash Lab Results
                                                                                                                                                                                              • Case Study 1 ndash Microscopy
                                                                                                                                                                                              • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                                              • Slide Number 105
                                                                                                                                                                                              • Slide Number 106
                                                                                                                                                                                              • Slide Number 107
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                                                                                                                                                                                              • Slide Number 109
                                                                                                                                                                                              • Slide Number 110
                                                                                                                                                                                              • Slide Number 111
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                                                                                                                                                                                              • Slide Number 113
                                                                                                                                                                                              • Slide Number 114
                                                                                                                                                                                              • Slide Number 115
                                                                                                                                                                                              • Slide Number 116
                                                                                                                                                                                              • Slide Number 117
                                                                                                                                                                                              • Slide Number 118
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                                                                                                                                                                                              • Slide Number 120
                                                                                                                                                                                              • Slide Number 121
                                                                                                                                                                                              • Slide Number 122
                                                                                                                                                                                              • Slide Number 123
                                                                                                                                                                                              • Slide Number 124
                                                                                                                                                                                              • Slide Number 125
                                                                                                                                                                                              • DIC Take Home Messages
                                                                                                                                                                                              • Slide Number 127
                                                                                                                                                                                              • Slide Number 128

                                                                                                                                                                                                Trends in Markers of DIC for Different Patients

                                                                                                                                                                                                Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00

                                                                                                                                                                                                Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients

                                                                                                                                                                                                Trends in Markers of DIC for Different Patients

                                                                                                                                                                                                Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                                                FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                                                                                                                28 day outcome survival

                                                                                                                                                                                                28 day outcome death

                                                                                                                                                                                                Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                                                                Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                                                                Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                                                                                                                Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                                                                Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                                                                Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                                                                                                                DIC Case Studies

                                                                                                                                                                                                Case Study 1 - Presentation

                                                                                                                                                                                                18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                                                                                                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                                Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                                                                                                WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                                                                                                RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                                                                                                Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                                                                                                Hematocrit 195 401 ndash 510

                                                                                                                                                                                                MCV 95 fL 790 ndash 922 fL

                                                                                                                                                                                                MPV 12 fL 94 ndash 124 fL

                                                                                                                                                                                                Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                                                                                                Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                                                                                                Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                                                                                                PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                                                                                                APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                                                                                                Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                                                                                                D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                                                                                                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                                Case Study 1 ndash Microscopy

                                                                                                                                                                                                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                                Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                                                                                                Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                                                                                                DIC due to TF release by APL blasts

                                                                                                                                                                                                Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                                                                                                Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                                                                                                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                                20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                                                                                                Case Study 2 ndash Presentation

                                                                                                                                                                                                TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                                                                                                PT 30 sec 113 ndash 146 sec

                                                                                                                                                                                                APTT 75 sec 25 ndash 34 sec

                                                                                                                                                                                                D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                                                                                                Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                                                                                                pH 728 738 to 742

                                                                                                                                                                                                PaO2 570 mmHg 80-100 mmHg

                                                                                                                                                                                                WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                                ALT 111 IUL 0ndash34 IUL

                                                                                                                                                                                                AST 61 IUL 0ndash34 IUL

                                                                                                                                                                                                BUN 303 mgdL 08-13 mgdL

                                                                                                                                                                                                Case Study 2 ndash Lab Results

                                                                                                                                                                                                Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                                                                                                Case Study 2 ndash Diagnosis

                                                                                                                                                                                                60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                                                                                                Case Study 3 ndash Presentation

                                                                                                                                                                                                TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                                                                                PT 228 sec 113 ndash 146 sec

                                                                                                                                                                                                APTT 45 sec 25 ndash 34 sec

                                                                                                                                                                                                D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                                                                                Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                                                                                FV Normal 70-120

                                                                                                                                                                                                FVII Normal 55-170

                                                                                                                                                                                                FVIII Normal 60-150

                                                                                                                                                                                                Protein C Normal 70-130

                                                                                                                                                                                                Hb 134 gdL 14-16 gdL

                                                                                                                                                                                                WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                                ALT 32 IUL 0ndash34 IUL

                                                                                                                                                                                                AST 28 IUL 0ndash34 IUL

                                                                                                                                                                                                BUN 09 mgdL 08-13 mgdL

                                                                                                                                                                                                Case Study 3 ndash Lab Results

                                                                                                                                                                                                Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                                                                                Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                                                                                Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                                                                                Case Study 4 ndash Presentation

                                                                                                                                                                                                TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                                                                                PT 28 sec 113 ndash 146 sec

                                                                                                                                                                                                APTT 71 sec 25 ndash 34 sec

                                                                                                                                                                                                D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                                                                                Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                                                                                FV Normal 70-120

                                                                                                                                                                                                FVII Normal 55-170

                                                                                                                                                                                                FVIII Normal 60-150

                                                                                                                                                                                                Protein C Normal 70-130

                                                                                                                                                                                                Hb 158 gdL 14-16 gdL

                                                                                                                                                                                                WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                                ALT 60 IUL 0ndash34 IUL

                                                                                                                                                                                                AST 47 IUL 0ndash34 IUL

                                                                                                                                                                                                BUN 38 mgdL 08-13 mgdL

                                                                                                                                                                                                Case Study 4 ndash Lab Results

                                                                                                                                                                                                Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                                                                                Case Study 4 ndash Diagnosis

                                                                                                                                                                                                55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                                                                                Case Study 5 ndash Presentation

                                                                                                                                                                                                Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                Case Study 5 ndash Lab Results and Time Course

                                                                                                                                                                                                Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                TEST RESULT REFERENCE RANGE

                                                                                                                                                                                                Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                                                                                PT 215 sec 103 ndash 128 sec

                                                                                                                                                                                                APTT 44 sec 26 ndash 36 sec

                                                                                                                                                                                                D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                                                                                Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                                                                                FII FV FVIII Low Not reported (NR)

                                                                                                                                                                                                FVII FIX FX vWF Normal NR

                                                                                                                                                                                                Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                                                                                DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                                                                                dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                                                                                (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                                                                                (D) Illustration demonstrating repair

                                                                                                                                                                                                Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                                                                                Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                                                                Case Study 6 ndash Presentation

                                                                                                                                                                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                Case Study 6 ndash Lab Results

                                                                                                                                                                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                                                                PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                                                                INR 658 1 ndash 125

                                                                                                                                                                                                APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                                                                D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                                                                Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                                                                Albumin 28 gdL NR

                                                                                                                                                                                                Hb 58 gdL NR

                                                                                                                                                                                                LDH 1196 UL NR

                                                                                                                                                                                                SGPT 144 IU NR

                                                                                                                                                                                                SGOT 88 IU NR

                                                                                                                                                                                                Bilirubin 32 mgdL NR

                                                                                                                                                                                                DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                                                                day postop

                                                                                                                                                                                                Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                                                                Case Study 6 ndash Discussion

                                                                                                                                                                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                                                                Case Study 7 ndash Presentation

                                                                                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                                                                Case Study 7 ndash Presentation

                                                                                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                Case Study 7 ndash Lab Results vs Time

                                                                                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                                                                Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                                                Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                DIC Take Home Messages

                                                                                                                                                                                                Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                                                Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                                                DIC

                                                                                                                                                                                                Thank you Questions

                                                                                                                                                                                                • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                                                • Learning Objectives
                                                                                                                                                                                                • Slide Number 3
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                                                                                                                                                                                                • Slide Number 8
                                                                                                                                                                                                • Wound Sealing
                                                                                                                                                                                                • The Three Steps of Hemostasis
                                                                                                                                                                                                • Vessel Wall
                                                                                                                                                                                                • Slide Number 12
                                                                                                                                                                                                • Slide Number 13
                                                                                                                                                                                                • Platelet Structure UnactivatedActivated
                                                                                                                                                                                                • Primary Hemostasis
                                                                                                                                                                                                • Primary Hemostasis Assays
                                                                                                                                                                                                • Slide Number 17
                                                                                                                                                                                                • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                                                • Slide Number 19
                                                                                                                                                                                                • Coagulation factors
                                                                                                                                                                                                • Coagulation Assay Mechanisms
                                                                                                                                                                                                • Slide Number 22
                                                                                                                                                                                                • Fibrin Formation
                                                                                                                                                                                                • Slide Number 24
                                                                                                                                                                                                • Fibrinolysis Overview
                                                                                                                                                                                                • Fibrinolysis Overview
                                                                                                                                                                                                • Slide Number 27
                                                                                                                                                                                                • Fibrinolysis Releases D-dimers
                                                                                                                                                                                                • Basic Pathophysiology of DIC
                                                                                                                                                                                                • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                                                • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                                                • Clinical Conditions Associated With DIC
                                                                                                                                                                                                • Frequency of DIC in Selected Disease States
                                                                                                                                                                                                • Underlying Diseases in DIC Patients
                                                                                                                                                                                                • Slide Number 36
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                                                                                                                                                                                                • Pathophysiology of DIC
                                                                                                                                                                                                • Pathogenesis of DIC in Sepsis
                                                                                                                                                                                                • Host Response in Severe Sepsis
                                                                                                                                                                                                • Organ Failure in Severe Sepsis
                                                                                                                                                                                                • Mechanism of DIC in Organ Failure
                                                                                                                                                                                                • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                                                • Slide Number 47
                                                                                                                                                                                                • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                                                • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                                                • Mechanism of DIC
                                                                                                                                                                                                • Pathophysiology of DIC
                                                                                                                                                                                                • Pathophysiology of DIC - Mechanism
                                                                                                                                                                                                • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                                                • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                                                • Pathophysiology of Overt DIC
                                                                                                                                                                                                • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                                                • Slide Number 57
                                                                                                                                                                                                • Slide Number 58
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                                                                                                                                                                                                • Slide Number 61
                                                                                                                                                                                                • BREAK
                                                                                                                                                                                                • Diagnostic and Management Approach for DIC
                                                                                                                                                                                                • Diagnosis of DIC
                                                                                                                                                                                                • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                                                • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                                                • Slide Number 67
                                                                                                                                                                                                • Slide Number 68
                                                                                                                                                                                                • British Journal of Haematology Overt DIC Score
                                                                                                                                                                                                • Slide Number 70
                                                                                                                                                                                                • Slide Number 71
                                                                                                                                                                                                • Slide Number 72
                                                                                                                                                                                                • Slide Number 73
                                                                                                                                                                                                • DIC Management Goals
                                                                                                                                                                                                • DIC Management and Treatment
                                                                                                                                                                                                • DIC Management Strategies
                                                                                                                                                                                                • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                                                • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                                                • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                                                • D-dimer FDPs and DIC
                                                                                                                                                                                                • D-Dimer and FDPs in DIC
                                                                                                                                                                                                • Follow Up of DIC State of Disease
                                                                                                                                                                                                • FMD-Dimer in DIC Major Differences
                                                                                                                                                                                                • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                                                • Slide Number 85
                                                                                                                                                                                                • Slide Number 86
                                                                                                                                                                                                • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                                                • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                • Slide Number 94
                                                                                                                                                                                                • Slide Number 95
                                                                                                                                                                                                • Slide Number 96
                                                                                                                                                                                                • Slide Number 97
                                                                                                                                                                                                • Slide Number 98
                                                                                                                                                                                                • Slide Number 99
                                                                                                                                                                                                • DIC Case Studies
                                                                                                                                                                                                • Case Study 1 - Presentation
                                                                                                                                                                                                • Case Study 1 ndash Lab Results
                                                                                                                                                                                                • Case Study 1 ndash Microscopy
                                                                                                                                                                                                • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                                                • Slide Number 105
                                                                                                                                                                                                • Slide Number 106
                                                                                                                                                                                                • Slide Number 107
                                                                                                                                                                                                • Slide Number 108
                                                                                                                                                                                                • Slide Number 109
                                                                                                                                                                                                • Slide Number 110
                                                                                                                                                                                                • Slide Number 111
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                                                                                                                                                                                                • Slide Number 113
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                                                                                                                                                                                                • Slide Number 120
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                                                                                                                                                                                                • Slide Number 122
                                                                                                                                                                                                • Slide Number 123
                                                                                                                                                                                                • Slide Number 124
                                                                                                                                                                                                • Slide Number 125
                                                                                                                                                                                                • DIC Take Home Messages
                                                                                                                                                                                                • Slide Number 127
                                                                                                                                                                                                • Slide Number 128

                                                                                                                                                                                                  Trends in Markers of DIC for Different Patients

                                                                                                                                                                                                  Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7

                                                                                                                                                                                                  FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes

                                                                                                                                                                                                  28 day outcome survival

                                                                                                                                                                                                  28 day outcome death

                                                                                                                                                                                                  Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                                                                  Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                                                                  Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                                                                                                                  Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                                                                  Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                                                                  Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                                                                                                                  DIC Case Studies

                                                                                                                                                                                                  Case Study 1 - Presentation

                                                                                                                                                                                                  18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                                                                                                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                                  Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                                                                                                  WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                                                                                                  RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                                                                                                  Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                                                                                                  Hematocrit 195 401 ndash 510

                                                                                                                                                                                                  MCV 95 fL 790 ndash 922 fL

                                                                                                                                                                                                  MPV 12 fL 94 ndash 124 fL

                                                                                                                                                                                                  Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                                                                                                  Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                                                                                                  Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                                                                                                  PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                                                                                                  APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                                                                                                  Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                                                                                                  D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                                                                                                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                                  Case Study 1 ndash Microscopy

                                                                                                                                                                                                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                                  Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                                                                                                  Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                                                                                                  DIC due to TF release by APL blasts

                                                                                                                                                                                                  Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                                                                                                  Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                                                                                                  Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                                  20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                                                                                                  Case Study 2 ndash Presentation

                                                                                                                                                                                                  TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                                                                                                  PT 30 sec 113 ndash 146 sec

                                                                                                                                                                                                  APTT 75 sec 25 ndash 34 sec

                                                                                                                                                                                                  D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                                                                                                  Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                                                                                                  pH 728 738 to 742

                                                                                                                                                                                                  PaO2 570 mmHg 80-100 mmHg

                                                                                                                                                                                                  WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                                  ALT 111 IUL 0ndash34 IUL

                                                                                                                                                                                                  AST 61 IUL 0ndash34 IUL

                                                                                                                                                                                                  BUN 303 mgdL 08-13 mgdL

                                                                                                                                                                                                  Case Study 2 ndash Lab Results

                                                                                                                                                                                                  Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                                                                                                  Case Study 2 ndash Diagnosis

                                                                                                                                                                                                  60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                                                                                                  Case Study 3 ndash Presentation

                                                                                                                                                                                                  TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                                                                                  PT 228 sec 113 ndash 146 sec

                                                                                                                                                                                                  APTT 45 sec 25 ndash 34 sec

                                                                                                                                                                                                  D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                                                                                  Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                                                                                  FV Normal 70-120

                                                                                                                                                                                                  FVII Normal 55-170

                                                                                                                                                                                                  FVIII Normal 60-150

                                                                                                                                                                                                  Protein C Normal 70-130

                                                                                                                                                                                                  Hb 134 gdL 14-16 gdL

                                                                                                                                                                                                  WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                                  ALT 32 IUL 0ndash34 IUL

                                                                                                                                                                                                  AST 28 IUL 0ndash34 IUL

                                                                                                                                                                                                  BUN 09 mgdL 08-13 mgdL

                                                                                                                                                                                                  Case Study 3 ndash Lab Results

                                                                                                                                                                                                  Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                                                                                  Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                                                                                  Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                                                                                  Case Study 4 ndash Presentation

                                                                                                                                                                                                  TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                                                                                  PT 28 sec 113 ndash 146 sec

                                                                                                                                                                                                  APTT 71 sec 25 ndash 34 sec

                                                                                                                                                                                                  D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                                                                                  Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                                                                                  FV Normal 70-120

                                                                                                                                                                                                  FVII Normal 55-170

                                                                                                                                                                                                  FVIII Normal 60-150

                                                                                                                                                                                                  Protein C Normal 70-130

                                                                                                                                                                                                  Hb 158 gdL 14-16 gdL

                                                                                                                                                                                                  WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                                  ALT 60 IUL 0ndash34 IUL

                                                                                                                                                                                                  AST 47 IUL 0ndash34 IUL

                                                                                                                                                                                                  BUN 38 mgdL 08-13 mgdL

                                                                                                                                                                                                  Case Study 4 ndash Lab Results

                                                                                                                                                                                                  Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                                                                                  Case Study 4 ndash Diagnosis

                                                                                                                                                                                                  55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                                                                                  Case Study 5 ndash Presentation

                                                                                                                                                                                                  Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                  Case Study 5 ndash Lab Results and Time Course

                                                                                                                                                                                                  Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                  TEST RESULT REFERENCE RANGE

                                                                                                                                                                                                  Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                                                                                  PT 215 sec 103 ndash 128 sec

                                                                                                                                                                                                  APTT 44 sec 26 ndash 36 sec

                                                                                                                                                                                                  D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                                                                                  Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                                                                                  FII FV FVIII Low Not reported (NR)

                                                                                                                                                                                                  FVII FIX FX vWF Normal NR

                                                                                                                                                                                                  Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                                                                                  DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                                                                                  dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                                                                                  (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                                                                                  (D) Illustration demonstrating repair

                                                                                                                                                                                                  Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                                                                                  Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                  29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                                                                  Case Study 6 ndash Presentation

                                                                                                                                                                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                  Case Study 6 ndash Lab Results

                                                                                                                                                                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                  TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                                                                  PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                                                                  INR 658 1 ndash 125

                                                                                                                                                                                                  APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                                                                  D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                                                                  Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                                                                  Albumin 28 gdL NR

                                                                                                                                                                                                  Hb 58 gdL NR

                                                                                                                                                                                                  LDH 1196 UL NR

                                                                                                                                                                                                  SGPT 144 IU NR

                                                                                                                                                                                                  SGOT 88 IU NR

                                                                                                                                                                                                  Bilirubin 32 mgdL NR

                                                                                                                                                                                                  DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                                                                  day postop

                                                                                                                                                                                                  Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                  HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                                                                  Case Study 6 ndash Discussion

                                                                                                                                                                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                  44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                                                                  Case Study 7 ndash Presentation

                                                                                                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                  On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                                                                  Case Study 7 ndash Presentation

                                                                                                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                  Case Study 7 ndash Lab Results vs Time

                                                                                                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                  Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                                                                  Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                  On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                                                  Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                  DIC Take Home Messages

                                                                                                                                                                                                  Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                                                  Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                                                  DIC

                                                                                                                                                                                                  Thank you Questions

                                                                                                                                                                                                  • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                                                  • Learning Objectives
                                                                                                                                                                                                  • Slide Number 3
                                                                                                                                                                                                  • Slide Number 4
                                                                                                                                                                                                  • Slide Number 5
                                                                                                                                                                                                  • Slide Number 6
                                                                                                                                                                                                  • Slide Number 7
                                                                                                                                                                                                  • Slide Number 8
                                                                                                                                                                                                  • Wound Sealing
                                                                                                                                                                                                  • The Three Steps of Hemostasis
                                                                                                                                                                                                  • Vessel Wall
                                                                                                                                                                                                  • Slide Number 12
                                                                                                                                                                                                  • Slide Number 13
                                                                                                                                                                                                  • Platelet Structure UnactivatedActivated
                                                                                                                                                                                                  • Primary Hemostasis
                                                                                                                                                                                                  • Primary Hemostasis Assays
                                                                                                                                                                                                  • Slide Number 17
                                                                                                                                                                                                  • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                                                  • Slide Number 19
                                                                                                                                                                                                  • Coagulation factors
                                                                                                                                                                                                  • Coagulation Assay Mechanisms
                                                                                                                                                                                                  • Slide Number 22
                                                                                                                                                                                                  • Fibrin Formation
                                                                                                                                                                                                  • Slide Number 24
                                                                                                                                                                                                  • Fibrinolysis Overview
                                                                                                                                                                                                  • Fibrinolysis Overview
                                                                                                                                                                                                  • Slide Number 27
                                                                                                                                                                                                  • Fibrinolysis Releases D-dimers
                                                                                                                                                                                                  • Basic Pathophysiology of DIC
                                                                                                                                                                                                  • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                                                  • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                                                  • Clinical Conditions Associated With DIC
                                                                                                                                                                                                  • Frequency of DIC in Selected Disease States
                                                                                                                                                                                                  • Underlying Diseases in DIC Patients
                                                                                                                                                                                                  • Slide Number 36
                                                                                                                                                                                                  • Slide Number 37
                                                                                                                                                                                                  • Slide Number 38
                                                                                                                                                                                                  • Slide Number 39
                                                                                                                                                                                                  • Pathophysiology of DIC
                                                                                                                                                                                                  • Pathogenesis of DIC in Sepsis
                                                                                                                                                                                                  • Host Response in Severe Sepsis
                                                                                                                                                                                                  • Organ Failure in Severe Sepsis
                                                                                                                                                                                                  • Mechanism of DIC in Organ Failure
                                                                                                                                                                                                  • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                                                  • Slide Number 47
                                                                                                                                                                                                  • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                                                  • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                                                  • Mechanism of DIC
                                                                                                                                                                                                  • Pathophysiology of DIC
                                                                                                                                                                                                  • Pathophysiology of DIC - Mechanism
                                                                                                                                                                                                  • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                                                  • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                                                  • Pathophysiology of Overt DIC
                                                                                                                                                                                                  • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                                                  • Slide Number 57
                                                                                                                                                                                                  • Slide Number 58
                                                                                                                                                                                                  • Slide Number 59
                                                                                                                                                                                                  • Slide Number 60
                                                                                                                                                                                                  • Slide Number 61
                                                                                                                                                                                                  • BREAK
                                                                                                                                                                                                  • Diagnostic and Management Approach for DIC
                                                                                                                                                                                                  • Diagnosis of DIC
                                                                                                                                                                                                  • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                                                  • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                                                  • Slide Number 67
                                                                                                                                                                                                  • Slide Number 68
                                                                                                                                                                                                  • British Journal of Haematology Overt DIC Score
                                                                                                                                                                                                  • Slide Number 70
                                                                                                                                                                                                  • Slide Number 71
                                                                                                                                                                                                  • Slide Number 72
                                                                                                                                                                                                  • Slide Number 73
                                                                                                                                                                                                  • DIC Management Goals
                                                                                                                                                                                                  • DIC Management and Treatment
                                                                                                                                                                                                  • DIC Management Strategies
                                                                                                                                                                                                  • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                                                  • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                                                  • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                                                  • D-dimer FDPs and DIC
                                                                                                                                                                                                  • D-Dimer and FDPs in DIC
                                                                                                                                                                                                  • Follow Up of DIC State of Disease
                                                                                                                                                                                                  • FMD-Dimer in DIC Major Differences
                                                                                                                                                                                                  • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                                                  • Slide Number 85
                                                                                                                                                                                                  • Slide Number 86
                                                                                                                                                                                                  • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                                                  • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                  • Slide Number 94
                                                                                                                                                                                                  • Slide Number 95
                                                                                                                                                                                                  • Slide Number 96
                                                                                                                                                                                                  • Slide Number 97
                                                                                                                                                                                                  • Slide Number 98
                                                                                                                                                                                                  • Slide Number 99
                                                                                                                                                                                                  • DIC Case Studies
                                                                                                                                                                                                  • Case Study 1 - Presentation
                                                                                                                                                                                                  • Case Study 1 ndash Lab Results
                                                                                                                                                                                                  • Case Study 1 ndash Microscopy
                                                                                                                                                                                                  • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                                                  • Slide Number 105
                                                                                                                                                                                                  • Slide Number 106
                                                                                                                                                                                                  • Slide Number 107
                                                                                                                                                                                                  • Slide Number 108
                                                                                                                                                                                                  • Slide Number 109
                                                                                                                                                                                                  • Slide Number 110
                                                                                                                                                                                                  • Slide Number 111
                                                                                                                                                                                                  • Slide Number 112
                                                                                                                                                                                                  • Slide Number 113
                                                                                                                                                                                                  • Slide Number 114
                                                                                                                                                                                                  • Slide Number 115
                                                                                                                                                                                                  • Slide Number 116
                                                                                                                                                                                                  • Slide Number 117
                                                                                                                                                                                                  • Slide Number 118
                                                                                                                                                                                                  • Slide Number 119
                                                                                                                                                                                                  • Slide Number 120
                                                                                                                                                                                                  • Slide Number 121
                                                                                                                                                                                                  • Slide Number 122
                                                                                                                                                                                                  • Slide Number 123
                                                                                                                                                                                                  • Slide Number 124
                                                                                                                                                                                                  • Slide Number 125
                                                                                                                                                                                                  • DIC Take Home Messages
                                                                                                                                                                                                  • Slide Number 127
                                                                                                                                                                                                  • Slide Number 128

                                                                                                                                                                                                    Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                                                                    Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                                                                    Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined

                                                                                                                                                                                                    Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                                                                    Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                                                                    Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                                                                                                                    DIC Case Studies

                                                                                                                                                                                                    Case Study 1 - Presentation

                                                                                                                                                                                                    18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                                                                                                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                                    Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                                                                                                    WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                                                                                                    RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                                                                                                    Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                                                                                                    Hematocrit 195 401 ndash 510

                                                                                                                                                                                                    MCV 95 fL 790 ndash 922 fL

                                                                                                                                                                                                    MPV 12 fL 94 ndash 124 fL

                                                                                                                                                                                                    Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                                                                                                    Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                                                                                                    Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                                                                                                    PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                                                                                                    APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                                                                                                    Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                                                                                                    D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                                                                                                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                                    Case Study 1 ndash Microscopy

                                                                                                                                                                                                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                                    Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                                                                                                    Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                                                                                                    DIC due to TF release by APL blasts

                                                                                                                                                                                                    Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                                                                                                    Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                                                                                                    Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                                    20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                                                                                                    Case Study 2 ndash Presentation

                                                                                                                                                                                                    TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                                                                                                    PT 30 sec 113 ndash 146 sec

                                                                                                                                                                                                    APTT 75 sec 25 ndash 34 sec

                                                                                                                                                                                                    D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                                                                                                    Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                                                                                                    pH 728 738 to 742

                                                                                                                                                                                                    PaO2 570 mmHg 80-100 mmHg

                                                                                                                                                                                                    WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                                    ALT 111 IUL 0ndash34 IUL

                                                                                                                                                                                                    AST 61 IUL 0ndash34 IUL

                                                                                                                                                                                                    BUN 303 mgdL 08-13 mgdL

                                                                                                                                                                                                    Case Study 2 ndash Lab Results

                                                                                                                                                                                                    Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                                                                                                    Case Study 2 ndash Diagnosis

                                                                                                                                                                                                    60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                                                                                                    Case Study 3 ndash Presentation

                                                                                                                                                                                                    TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                                                                                    PT 228 sec 113 ndash 146 sec

                                                                                                                                                                                                    APTT 45 sec 25 ndash 34 sec

                                                                                                                                                                                                    D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                                                                                    Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                                                                                    FV Normal 70-120

                                                                                                                                                                                                    FVII Normal 55-170

                                                                                                                                                                                                    FVIII Normal 60-150

                                                                                                                                                                                                    Protein C Normal 70-130

                                                                                                                                                                                                    Hb 134 gdL 14-16 gdL

                                                                                                                                                                                                    WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                                    ALT 32 IUL 0ndash34 IUL

                                                                                                                                                                                                    AST 28 IUL 0ndash34 IUL

                                                                                                                                                                                                    BUN 09 mgdL 08-13 mgdL

                                                                                                                                                                                                    Case Study 3 ndash Lab Results

                                                                                                                                                                                                    Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                                                                                    Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                                                                                    Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                                                                                    Case Study 4 ndash Presentation

                                                                                                                                                                                                    TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                                                                                    PT 28 sec 113 ndash 146 sec

                                                                                                                                                                                                    APTT 71 sec 25 ndash 34 sec

                                                                                                                                                                                                    D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                                                                                    Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                                                                                    FV Normal 70-120

                                                                                                                                                                                                    FVII Normal 55-170

                                                                                                                                                                                                    FVIII Normal 60-150

                                                                                                                                                                                                    Protein C Normal 70-130

                                                                                                                                                                                                    Hb 158 gdL 14-16 gdL

                                                                                                                                                                                                    WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                                    ALT 60 IUL 0ndash34 IUL

                                                                                                                                                                                                    AST 47 IUL 0ndash34 IUL

                                                                                                                                                                                                    BUN 38 mgdL 08-13 mgdL

                                                                                                                                                                                                    Case Study 4 ndash Lab Results

                                                                                                                                                                                                    Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                                                                                    Case Study 4 ndash Diagnosis

                                                                                                                                                                                                    55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                                                                                    Case Study 5 ndash Presentation

                                                                                                                                                                                                    Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                    Case Study 5 ndash Lab Results and Time Course

                                                                                                                                                                                                    Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                    TEST RESULT REFERENCE RANGE

                                                                                                                                                                                                    Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                                                                                    PT 215 sec 103 ndash 128 sec

                                                                                                                                                                                                    APTT 44 sec 26 ndash 36 sec

                                                                                                                                                                                                    D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                                                                                    Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                                                                                    FII FV FVIII Low Not reported (NR)

                                                                                                                                                                                                    FVII FIX FX vWF Normal NR

                                                                                                                                                                                                    Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                                                                                    DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                                                                                    dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                                                                                    (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                                                                                    (D) Illustration demonstrating repair

                                                                                                                                                                                                    Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                                                                                    Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                    29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                                                                    Case Study 6 ndash Presentation

                                                                                                                                                                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                    Case Study 6 ndash Lab Results

                                                                                                                                                                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                    TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                                                                    PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                                                                    INR 658 1 ndash 125

                                                                                                                                                                                                    APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                                                                    D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                                                                    Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                                                                    Albumin 28 gdL NR

                                                                                                                                                                                                    Hb 58 gdL NR

                                                                                                                                                                                                    LDH 1196 UL NR

                                                                                                                                                                                                    SGPT 144 IU NR

                                                                                                                                                                                                    SGOT 88 IU NR

                                                                                                                                                                                                    Bilirubin 32 mgdL NR

                                                                                                                                                                                                    DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                                                                    day postop

                                                                                                                                                                                                    Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                    HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                                                                    Case Study 6 ndash Discussion

                                                                                                                                                                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                    44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                                                                    Case Study 7 ndash Presentation

                                                                                                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                    On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                                                                    Case Study 7 ndash Presentation

                                                                                                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                    Case Study 7 ndash Lab Results vs Time

                                                                                                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                    Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                                                                    Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                    On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                                                    Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                    DIC Take Home Messages

                                                                                                                                                                                                    Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                                                    Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                                                    DIC

                                                                                                                                                                                                    Thank you Questions

                                                                                                                                                                                                    • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                                                    • Learning Objectives
                                                                                                                                                                                                    • Slide Number 3
                                                                                                                                                                                                    • Slide Number 4
                                                                                                                                                                                                    • Slide Number 5
                                                                                                                                                                                                    • Slide Number 6
                                                                                                                                                                                                    • Slide Number 7
                                                                                                                                                                                                    • Slide Number 8
                                                                                                                                                                                                    • Wound Sealing
                                                                                                                                                                                                    • The Three Steps of Hemostasis
                                                                                                                                                                                                    • Vessel Wall
                                                                                                                                                                                                    • Slide Number 12
                                                                                                                                                                                                    • Slide Number 13
                                                                                                                                                                                                    • Platelet Structure UnactivatedActivated
                                                                                                                                                                                                    • Primary Hemostasis
                                                                                                                                                                                                    • Primary Hemostasis Assays
                                                                                                                                                                                                    • Slide Number 17
                                                                                                                                                                                                    • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                                                    • Slide Number 19
                                                                                                                                                                                                    • Coagulation factors
                                                                                                                                                                                                    • Coagulation Assay Mechanisms
                                                                                                                                                                                                    • Slide Number 22
                                                                                                                                                                                                    • Fibrin Formation
                                                                                                                                                                                                    • Slide Number 24
                                                                                                                                                                                                    • Fibrinolysis Overview
                                                                                                                                                                                                    • Fibrinolysis Overview
                                                                                                                                                                                                    • Slide Number 27
                                                                                                                                                                                                    • Fibrinolysis Releases D-dimers
                                                                                                                                                                                                    • Basic Pathophysiology of DIC
                                                                                                                                                                                                    • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                                                    • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                                                    • Clinical Conditions Associated With DIC
                                                                                                                                                                                                    • Frequency of DIC in Selected Disease States
                                                                                                                                                                                                    • Underlying Diseases in DIC Patients
                                                                                                                                                                                                    • Slide Number 36
                                                                                                                                                                                                    • Slide Number 37
                                                                                                                                                                                                    • Slide Number 38
                                                                                                                                                                                                    • Slide Number 39
                                                                                                                                                                                                    • Pathophysiology of DIC
                                                                                                                                                                                                    • Pathogenesis of DIC in Sepsis
                                                                                                                                                                                                    • Host Response in Severe Sepsis
                                                                                                                                                                                                    • Organ Failure in Severe Sepsis
                                                                                                                                                                                                    • Mechanism of DIC in Organ Failure
                                                                                                                                                                                                    • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                                                    • Slide Number 47
                                                                                                                                                                                                    • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                                                    • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                                                    • Mechanism of DIC
                                                                                                                                                                                                    • Pathophysiology of DIC
                                                                                                                                                                                                    • Pathophysiology of DIC - Mechanism
                                                                                                                                                                                                    • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                                                    • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                                                    • Pathophysiology of Overt DIC
                                                                                                                                                                                                    • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                                                    • Slide Number 57
                                                                                                                                                                                                    • Slide Number 58
                                                                                                                                                                                                    • Slide Number 59
                                                                                                                                                                                                    • Slide Number 60
                                                                                                                                                                                                    • Slide Number 61
                                                                                                                                                                                                    • BREAK
                                                                                                                                                                                                    • Diagnostic and Management Approach for DIC
                                                                                                                                                                                                    • Diagnosis of DIC
                                                                                                                                                                                                    • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                                                    • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                                                    • Slide Number 67
                                                                                                                                                                                                    • Slide Number 68
                                                                                                                                                                                                    • British Journal of Haematology Overt DIC Score
                                                                                                                                                                                                    • Slide Number 70
                                                                                                                                                                                                    • Slide Number 71
                                                                                                                                                                                                    • Slide Number 72
                                                                                                                                                                                                    • Slide Number 73
                                                                                                                                                                                                    • DIC Management Goals
                                                                                                                                                                                                    • DIC Management and Treatment
                                                                                                                                                                                                    • DIC Management Strategies
                                                                                                                                                                                                    • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                                                    • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                                                    • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                                                    • D-dimer FDPs and DIC
                                                                                                                                                                                                    • D-Dimer and FDPs in DIC
                                                                                                                                                                                                    • Follow Up of DIC State of Disease
                                                                                                                                                                                                    • FMD-Dimer in DIC Major Differences
                                                                                                                                                                                                    • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                                                    • Slide Number 85
                                                                                                                                                                                                    • Slide Number 86
                                                                                                                                                                                                    • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                                                    • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                    • Slide Number 94
                                                                                                                                                                                                    • Slide Number 95
                                                                                                                                                                                                    • Slide Number 96
                                                                                                                                                                                                    • Slide Number 97
                                                                                                                                                                                                    • Slide Number 98
                                                                                                                                                                                                    • Slide Number 99
                                                                                                                                                                                                    • DIC Case Studies
                                                                                                                                                                                                    • Case Study 1 - Presentation
                                                                                                                                                                                                    • Case Study 1 ndash Lab Results
                                                                                                                                                                                                    • Case Study 1 ndash Microscopy
                                                                                                                                                                                                    • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                                                    • Slide Number 105
                                                                                                                                                                                                    • Slide Number 106
                                                                                                                                                                                                    • Slide Number 107
                                                                                                                                                                                                    • Slide Number 108
                                                                                                                                                                                                    • Slide Number 109
                                                                                                                                                                                                    • Slide Number 110
                                                                                                                                                                                                    • Slide Number 111
                                                                                                                                                                                                    • Slide Number 112
                                                                                                                                                                                                    • Slide Number 113
                                                                                                                                                                                                    • Slide Number 114
                                                                                                                                                                                                    • Slide Number 115
                                                                                                                                                                                                    • Slide Number 116
                                                                                                                                                                                                    • Slide Number 117
                                                                                                                                                                                                    • Slide Number 118
                                                                                                                                                                                                    • Slide Number 119
                                                                                                                                                                                                    • Slide Number 120
                                                                                                                                                                                                    • Slide Number 121
                                                                                                                                                                                                    • Slide Number 122
                                                                                                                                                                                                    • Slide Number 123
                                                                                                                                                                                                    • Slide Number 124
                                                                                                                                                                                                    • Slide Number 125
                                                                                                                                                                                                    • DIC Take Home Messages
                                                                                                                                                                                                    • Slide Number 127
                                                                                                                                                                                                    • Slide Number 128

                                                                                                                                                                                                      Determination of Cutoffs of FM and D-dimer in DIC

                                                                                                                                                                                                      Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500

                                                                                                                                                                                                      Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines

                                                                                                                                                                                                      DIC Case Studies

                                                                                                                                                                                                      Case Study 1 - Presentation

                                                                                                                                                                                                      18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                                                                                                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                                      Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                                                                                                      WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                                                                                                      RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                                                                                                      Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                                                                                                      Hematocrit 195 401 ndash 510

                                                                                                                                                                                                      MCV 95 fL 790 ndash 922 fL

                                                                                                                                                                                                      MPV 12 fL 94 ndash 124 fL

                                                                                                                                                                                                      Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                                                                                                      Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                                                                                                      Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                                                                                                      PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                                                                                                      APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                                                                                                      Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                                                                                                      D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                                                                                                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                                      Case Study 1 ndash Microscopy

                                                                                                                                                                                                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                                      Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                                                                                                      Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                                                                                                      DIC due to TF release by APL blasts

                                                                                                                                                                                                      Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                                                                                                      Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                                                                                                      Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                                      20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                                                                                                      Case Study 2 ndash Presentation

                                                                                                                                                                                                      TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                                                                                                      PT 30 sec 113 ndash 146 sec

                                                                                                                                                                                                      APTT 75 sec 25 ndash 34 sec

                                                                                                                                                                                                      D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                                                                                                      Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                                                                                                      pH 728 738 to 742

                                                                                                                                                                                                      PaO2 570 mmHg 80-100 mmHg

                                                                                                                                                                                                      WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                                      ALT 111 IUL 0ndash34 IUL

                                                                                                                                                                                                      AST 61 IUL 0ndash34 IUL

                                                                                                                                                                                                      BUN 303 mgdL 08-13 mgdL

                                                                                                                                                                                                      Case Study 2 ndash Lab Results

                                                                                                                                                                                                      Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                                                                                                      Case Study 2 ndash Diagnosis

                                                                                                                                                                                                      60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                                                                                                      Case Study 3 ndash Presentation

                                                                                                                                                                                                      TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                                                                                      PT 228 sec 113 ndash 146 sec

                                                                                                                                                                                                      APTT 45 sec 25 ndash 34 sec

                                                                                                                                                                                                      D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                                                                                      Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                                                                                      FV Normal 70-120

                                                                                                                                                                                                      FVII Normal 55-170

                                                                                                                                                                                                      FVIII Normal 60-150

                                                                                                                                                                                                      Protein C Normal 70-130

                                                                                                                                                                                                      Hb 134 gdL 14-16 gdL

                                                                                                                                                                                                      WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                                      ALT 32 IUL 0ndash34 IUL

                                                                                                                                                                                                      AST 28 IUL 0ndash34 IUL

                                                                                                                                                                                                      BUN 09 mgdL 08-13 mgdL

                                                                                                                                                                                                      Case Study 3 ndash Lab Results

                                                                                                                                                                                                      Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                                                                                      Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                                                                                      Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                                                                                      Case Study 4 ndash Presentation

                                                                                                                                                                                                      TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                                                                                      PT 28 sec 113 ndash 146 sec

                                                                                                                                                                                                      APTT 71 sec 25 ndash 34 sec

                                                                                                                                                                                                      D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                                                                                      Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                                                                                      FV Normal 70-120

                                                                                                                                                                                                      FVII Normal 55-170

                                                                                                                                                                                                      FVIII Normal 60-150

                                                                                                                                                                                                      Protein C Normal 70-130

                                                                                                                                                                                                      Hb 158 gdL 14-16 gdL

                                                                                                                                                                                                      WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                                      ALT 60 IUL 0ndash34 IUL

                                                                                                                                                                                                      AST 47 IUL 0ndash34 IUL

                                                                                                                                                                                                      BUN 38 mgdL 08-13 mgdL

                                                                                                                                                                                                      Case Study 4 ndash Lab Results

                                                                                                                                                                                                      Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                                                                                      Case Study 4 ndash Diagnosis

                                                                                                                                                                                                      55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                                                                                      Case Study 5 ndash Presentation

                                                                                                                                                                                                      Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                      Case Study 5 ndash Lab Results and Time Course

                                                                                                                                                                                                      Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                      TEST RESULT REFERENCE RANGE

                                                                                                                                                                                                      Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                                                                                      PT 215 sec 103 ndash 128 sec

                                                                                                                                                                                                      APTT 44 sec 26 ndash 36 sec

                                                                                                                                                                                                      D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                                                                                      Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                                                                                      FII FV FVIII Low Not reported (NR)

                                                                                                                                                                                                      FVII FIX FX vWF Normal NR

                                                                                                                                                                                                      Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                                                                                      DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                                                                                      dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                                                                                      (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                                                                                      (D) Illustration demonstrating repair

                                                                                                                                                                                                      Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                                                                                      Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                      29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                                                                      Case Study 6 ndash Presentation

                                                                                                                                                                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                      Case Study 6 ndash Lab Results

                                                                                                                                                                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                      TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                                                                      PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                                                                      INR 658 1 ndash 125

                                                                                                                                                                                                      APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                                                                      D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                                                                      Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                                                                      Albumin 28 gdL NR

                                                                                                                                                                                                      Hb 58 gdL NR

                                                                                                                                                                                                      LDH 1196 UL NR

                                                                                                                                                                                                      SGPT 144 IU NR

                                                                                                                                                                                                      SGOT 88 IU NR

                                                                                                                                                                                                      Bilirubin 32 mgdL NR

                                                                                                                                                                                                      DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                                                                      day postop

                                                                                                                                                                                                      Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                      HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                                                                      Case Study 6 ndash Discussion

                                                                                                                                                                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                      44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                                                                      Case Study 7 ndash Presentation

                                                                                                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                      On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                                                                      Case Study 7 ndash Presentation

                                                                                                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                      Case Study 7 ndash Lab Results vs Time

                                                                                                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                      Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                                                                      Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                      On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                                                      Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                      DIC Take Home Messages

                                                                                                                                                                                                      Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                                                      Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                                                      DIC

                                                                                                                                                                                                      Thank you Questions

                                                                                                                                                                                                      • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                                                      • Learning Objectives
                                                                                                                                                                                                      • Slide Number 3
                                                                                                                                                                                                      • Slide Number 4
                                                                                                                                                                                                      • Slide Number 5
                                                                                                                                                                                                      • Slide Number 6
                                                                                                                                                                                                      • Slide Number 7
                                                                                                                                                                                                      • Slide Number 8
                                                                                                                                                                                                      • Wound Sealing
                                                                                                                                                                                                      • The Three Steps of Hemostasis
                                                                                                                                                                                                      • Vessel Wall
                                                                                                                                                                                                      • Slide Number 12
                                                                                                                                                                                                      • Slide Number 13
                                                                                                                                                                                                      • Platelet Structure UnactivatedActivated
                                                                                                                                                                                                      • Primary Hemostasis
                                                                                                                                                                                                      • Primary Hemostasis Assays
                                                                                                                                                                                                      • Slide Number 17
                                                                                                                                                                                                      • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                                                      • Slide Number 19
                                                                                                                                                                                                      • Coagulation factors
                                                                                                                                                                                                      • Coagulation Assay Mechanisms
                                                                                                                                                                                                      • Slide Number 22
                                                                                                                                                                                                      • Fibrin Formation
                                                                                                                                                                                                      • Slide Number 24
                                                                                                                                                                                                      • Fibrinolysis Overview
                                                                                                                                                                                                      • Fibrinolysis Overview
                                                                                                                                                                                                      • Slide Number 27
                                                                                                                                                                                                      • Fibrinolysis Releases D-dimers
                                                                                                                                                                                                      • Basic Pathophysiology of DIC
                                                                                                                                                                                                      • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                                                      • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                                                      • Clinical Conditions Associated With DIC
                                                                                                                                                                                                      • Frequency of DIC in Selected Disease States
                                                                                                                                                                                                      • Underlying Diseases in DIC Patients
                                                                                                                                                                                                      • Slide Number 36
                                                                                                                                                                                                      • Slide Number 37
                                                                                                                                                                                                      • Slide Number 38
                                                                                                                                                                                                      • Slide Number 39
                                                                                                                                                                                                      • Pathophysiology of DIC
                                                                                                                                                                                                      • Pathogenesis of DIC in Sepsis
                                                                                                                                                                                                      • Host Response in Severe Sepsis
                                                                                                                                                                                                      • Organ Failure in Severe Sepsis
                                                                                                                                                                                                      • Mechanism of DIC in Organ Failure
                                                                                                                                                                                                      • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                                                      • Slide Number 47
                                                                                                                                                                                                      • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                                                      • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                                                      • Mechanism of DIC
                                                                                                                                                                                                      • Pathophysiology of DIC
                                                                                                                                                                                                      • Pathophysiology of DIC - Mechanism
                                                                                                                                                                                                      • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                                                      • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                                                      • Pathophysiology of Overt DIC
                                                                                                                                                                                                      • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                                                      • Slide Number 57
                                                                                                                                                                                                      • Slide Number 58
                                                                                                                                                                                                      • Slide Number 59
                                                                                                                                                                                                      • Slide Number 60
                                                                                                                                                                                                      • Slide Number 61
                                                                                                                                                                                                      • BREAK
                                                                                                                                                                                                      • Diagnostic and Management Approach for DIC
                                                                                                                                                                                                      • Diagnosis of DIC
                                                                                                                                                                                                      • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                                                      • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                                                      • Slide Number 67
                                                                                                                                                                                                      • Slide Number 68
                                                                                                                                                                                                      • British Journal of Haematology Overt DIC Score
                                                                                                                                                                                                      • Slide Number 70
                                                                                                                                                                                                      • Slide Number 71
                                                                                                                                                                                                      • Slide Number 72
                                                                                                                                                                                                      • Slide Number 73
                                                                                                                                                                                                      • DIC Management Goals
                                                                                                                                                                                                      • DIC Management and Treatment
                                                                                                                                                                                                      • DIC Management Strategies
                                                                                                                                                                                                      • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                                                      • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                                                      • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                                                      • D-dimer FDPs and DIC
                                                                                                                                                                                                      • D-Dimer and FDPs in DIC
                                                                                                                                                                                                      • Follow Up of DIC State of Disease
                                                                                                                                                                                                      • FMD-Dimer in DIC Major Differences
                                                                                                                                                                                                      • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                                                      • Slide Number 85
                                                                                                                                                                                                      • Slide Number 86
                                                                                                                                                                                                      • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                                                      • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                      • Slide Number 94
                                                                                                                                                                                                      • Slide Number 95
                                                                                                                                                                                                      • Slide Number 96
                                                                                                                                                                                                      • Slide Number 97
                                                                                                                                                                                                      • Slide Number 98
                                                                                                                                                                                                      • Slide Number 99
                                                                                                                                                                                                      • DIC Case Studies
                                                                                                                                                                                                      • Case Study 1 - Presentation
                                                                                                                                                                                                      • Case Study 1 ndash Lab Results
                                                                                                                                                                                                      • Case Study 1 ndash Microscopy
                                                                                                                                                                                                      • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                                                      • Slide Number 105
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                                                                                                                                                                                                      • DIC Take Home Messages
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                                                                                                                                                                                                        DIC Case Studies

                                                                                                                                                                                                        Case Study 1 - Presentation

                                                                                                                                                                                                        18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                                                                                                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                                        Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                                                                                                        WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                                                                                                        RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                                                                                                        Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                                                                                                        Hematocrit 195 401 ndash 510

                                                                                                                                                                                                        MCV 95 fL 790 ndash 922 fL

                                                                                                                                                                                                        MPV 12 fL 94 ndash 124 fL

                                                                                                                                                                                                        Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                                                                                                        Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                                                                                                        Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                                                                                                        PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                                                                                                        APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                                                                                                        Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                                                                                                        D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                                                                                                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                                        Case Study 1 ndash Microscopy

                                                                                                                                                                                                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                                        Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                                                                                                        Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                                                                                                        DIC due to TF release by APL blasts

                                                                                                                                                                                                        Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                                                                                                        Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                                                                                                        Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                                        20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                                                                                                        Case Study 2 ndash Presentation

                                                                                                                                                                                                        TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                                                                                                        PT 30 sec 113 ndash 146 sec

                                                                                                                                                                                                        APTT 75 sec 25 ndash 34 sec

                                                                                                                                                                                                        D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                                                                                                        Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                                                                                                        pH 728 738 to 742

                                                                                                                                                                                                        PaO2 570 mmHg 80-100 mmHg

                                                                                                                                                                                                        WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                                        ALT 111 IUL 0ndash34 IUL

                                                                                                                                                                                                        AST 61 IUL 0ndash34 IUL

                                                                                                                                                                                                        BUN 303 mgdL 08-13 mgdL

                                                                                                                                                                                                        Case Study 2 ndash Lab Results

                                                                                                                                                                                                        Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                                                                                                        Case Study 2 ndash Diagnosis

                                                                                                                                                                                                        60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                                                                                                        Case Study 3 ndash Presentation

                                                                                                                                                                                                        TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                                                                                        PT 228 sec 113 ndash 146 sec

                                                                                                                                                                                                        APTT 45 sec 25 ndash 34 sec

                                                                                                                                                                                                        D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                                                                                        Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                                                                                        FV Normal 70-120

                                                                                                                                                                                                        FVII Normal 55-170

                                                                                                                                                                                                        FVIII Normal 60-150

                                                                                                                                                                                                        Protein C Normal 70-130

                                                                                                                                                                                                        Hb 134 gdL 14-16 gdL

                                                                                                                                                                                                        WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                                        ALT 32 IUL 0ndash34 IUL

                                                                                                                                                                                                        AST 28 IUL 0ndash34 IUL

                                                                                                                                                                                                        BUN 09 mgdL 08-13 mgdL

                                                                                                                                                                                                        Case Study 3 ndash Lab Results

                                                                                                                                                                                                        Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                                                                                        Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                                                                                        Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                                                                                        Case Study 4 ndash Presentation

                                                                                                                                                                                                        TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                                                                                        PT 28 sec 113 ndash 146 sec

                                                                                                                                                                                                        APTT 71 sec 25 ndash 34 sec

                                                                                                                                                                                                        D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                                                                                        Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                                                                                        FV Normal 70-120

                                                                                                                                                                                                        FVII Normal 55-170

                                                                                                                                                                                                        FVIII Normal 60-150

                                                                                                                                                                                                        Protein C Normal 70-130

                                                                                                                                                                                                        Hb 158 gdL 14-16 gdL

                                                                                                                                                                                                        WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                                        ALT 60 IUL 0ndash34 IUL

                                                                                                                                                                                                        AST 47 IUL 0ndash34 IUL

                                                                                                                                                                                                        BUN 38 mgdL 08-13 mgdL

                                                                                                                                                                                                        Case Study 4 ndash Lab Results

                                                                                                                                                                                                        Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                                                                                        Case Study 4 ndash Diagnosis

                                                                                                                                                                                                        55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                                                                                        Case Study 5 ndash Presentation

                                                                                                                                                                                                        Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                        Case Study 5 ndash Lab Results and Time Course

                                                                                                                                                                                                        Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                        TEST RESULT REFERENCE RANGE

                                                                                                                                                                                                        Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                                                                                        PT 215 sec 103 ndash 128 sec

                                                                                                                                                                                                        APTT 44 sec 26 ndash 36 sec

                                                                                                                                                                                                        D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                                                                                        Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                                                                                        FII FV FVIII Low Not reported (NR)

                                                                                                                                                                                                        FVII FIX FX vWF Normal NR

                                                                                                                                                                                                        Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                                                                                        DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                                                                                        dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                                                                                        (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                                                                                        (D) Illustration demonstrating repair

                                                                                                                                                                                                        Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                                                                                        Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                        29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                                                                        Case Study 6 ndash Presentation

                                                                                                                                                                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                        Case Study 6 ndash Lab Results

                                                                                                                                                                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                        TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                                                                        PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                                                                        INR 658 1 ndash 125

                                                                                                                                                                                                        APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                                                                        D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                                                                        Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                                                                        Albumin 28 gdL NR

                                                                                                                                                                                                        Hb 58 gdL NR

                                                                                                                                                                                                        LDH 1196 UL NR

                                                                                                                                                                                                        SGPT 144 IU NR

                                                                                                                                                                                                        SGOT 88 IU NR

                                                                                                                                                                                                        Bilirubin 32 mgdL NR

                                                                                                                                                                                                        DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                                                                        day postop

                                                                                                                                                                                                        Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                        HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                                                                        Case Study 6 ndash Discussion

                                                                                                                                                                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                        44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                                                                        Case Study 7 ndash Presentation

                                                                                                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                        On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                                                                        Case Study 7 ndash Presentation

                                                                                                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                        Case Study 7 ndash Lab Results vs Time

                                                                                                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                        Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                                                                        Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                        On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                                                        Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                        DIC Take Home Messages

                                                                                                                                                                                                        Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                                                        Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                                                        DIC

                                                                                                                                                                                                        Thank you Questions

                                                                                                                                                                                                        • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                                                        • Learning Objectives
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                                                                                                                                                                                                        • Wound Sealing
                                                                                                                                                                                                        • The Three Steps of Hemostasis
                                                                                                                                                                                                        • Vessel Wall
                                                                                                                                                                                                        • Slide Number 12
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                                                                                                                                                                                                        • Platelet Structure UnactivatedActivated
                                                                                                                                                                                                        • Primary Hemostasis
                                                                                                                                                                                                        • Primary Hemostasis Assays
                                                                                                                                                                                                        • Slide Number 17
                                                                                                                                                                                                        • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
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                                                                                                                                                                                                        • Coagulation factors
                                                                                                                                                                                                        • Coagulation Assay Mechanisms
                                                                                                                                                                                                        • Slide Number 22
                                                                                                                                                                                                        • Fibrin Formation
                                                                                                                                                                                                        • Slide Number 24
                                                                                                                                                                                                        • Fibrinolysis Overview
                                                                                                                                                                                                        • Fibrinolysis Overview
                                                                                                                                                                                                        • Slide Number 27
                                                                                                                                                                                                        • Fibrinolysis Releases D-dimers
                                                                                                                                                                                                        • Basic Pathophysiology of DIC
                                                                                                                                                                                                        • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                                                        • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                                                        • Clinical Conditions Associated With DIC
                                                                                                                                                                                                        • Frequency of DIC in Selected Disease States
                                                                                                                                                                                                        • Underlying Diseases in DIC Patients
                                                                                                                                                                                                        • Slide Number 36
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                                                                                                                                                                                                        • Pathophysiology of DIC
                                                                                                                                                                                                        • Pathogenesis of DIC in Sepsis
                                                                                                                                                                                                        • Host Response in Severe Sepsis
                                                                                                                                                                                                        • Organ Failure in Severe Sepsis
                                                                                                                                                                                                        • Mechanism of DIC in Organ Failure
                                                                                                                                                                                                        • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                                                        • Slide Number 47
                                                                                                                                                                                                        • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                                                        • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                                                        • Mechanism of DIC
                                                                                                                                                                                                        • Pathophysiology of DIC
                                                                                                                                                                                                        • Pathophysiology of DIC - Mechanism
                                                                                                                                                                                                        • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                                                        • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                                                        • Pathophysiology of Overt DIC
                                                                                                                                                                                                        • Physiopathology of DIC ndash Overt DIC Findings
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                                                                                                                                                                                                        • BREAK
                                                                                                                                                                                                        • Diagnostic and Management Approach for DIC
                                                                                                                                                                                                        • Diagnosis of DIC
                                                                                                                                                                                                        • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                                                        • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                                                        • Slide Number 67
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                                                                                                                                                                                                        • British Journal of Haematology Overt DIC Score
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                                                                                                                                                                                                        • DIC Management Goals
                                                                                                                                                                                                        • DIC Management and Treatment
                                                                                                                                                                                                        • DIC Management Strategies
                                                                                                                                                                                                        • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                                                        • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                                                        • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                                                        • D-dimer FDPs and DIC
                                                                                                                                                                                                        • D-Dimer and FDPs in DIC
                                                                                                                                                                                                        • Follow Up of DIC State of Disease
                                                                                                                                                                                                        • FMD-Dimer in DIC Major Differences
                                                                                                                                                                                                        • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                                                        • Slide Number 85
                                                                                                                                                                                                        • Slide Number 86
                                                                                                                                                                                                        • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                                                        • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                        • Slide Number 94
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                                                                                                                                                                                                        • Slide Number 96
                                                                                                                                                                                                        • Slide Number 97
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                                                                                                                                                                                                        • Slide Number 99
                                                                                                                                                                                                        • DIC Case Studies
                                                                                                                                                                                                        • Case Study 1 - Presentation
                                                                                                                                                                                                        • Case Study 1 ndash Lab Results
                                                                                                                                                                                                        • Case Study 1 ndash Microscopy
                                                                                                                                                                                                        • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                                                        • Slide Number 105
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                                                                                                                                                                                                        • Slide Number 123
                                                                                                                                                                                                        • Slide Number 124
                                                                                                                                                                                                        • Slide Number 125
                                                                                                                                                                                                        • DIC Take Home Messages
                                                                                                                                                                                                        • Slide Number 127
                                                                                                                                                                                                        • Slide Number 128

                                                                                                                                                                                                          Case Study 1 - Presentation

                                                                                                                                                                                                          18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered

                                                                                                                                                                                                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                                          Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                                                                                                          WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                                                                                                          RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                                                                                                          Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                                                                                                          Hematocrit 195 401 ndash 510

                                                                                                                                                                                                          MCV 95 fL 790 ndash 922 fL

                                                                                                                                                                                                          MPV 12 fL 94 ndash 124 fL

                                                                                                                                                                                                          Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                                                                                                          Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                                                                                                          Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                                                                                                          PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                                                                                                          APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                                                                                                          Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                                                                                                          D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                                                                                                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                                          Case Study 1 ndash Microscopy

                                                                                                                                                                                                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                                          Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                                                                                                          Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                                                                                                          DIC due to TF release by APL blasts

                                                                                                                                                                                                          Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                                                                                                          Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                                                                                                          Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                                          20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                                                                                                          Case Study 2 ndash Presentation

                                                                                                                                                                                                          TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                                                                                                          PT 30 sec 113 ndash 146 sec

                                                                                                                                                                                                          APTT 75 sec 25 ndash 34 sec

                                                                                                                                                                                                          D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                                                                                                          Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                                                                                                          pH 728 738 to 742

                                                                                                                                                                                                          PaO2 570 mmHg 80-100 mmHg

                                                                                                                                                                                                          WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                                          ALT 111 IUL 0ndash34 IUL

                                                                                                                                                                                                          AST 61 IUL 0ndash34 IUL

                                                                                                                                                                                                          BUN 303 mgdL 08-13 mgdL

                                                                                                                                                                                                          Case Study 2 ndash Lab Results

                                                                                                                                                                                                          Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                                                                                                          Case Study 2 ndash Diagnosis

                                                                                                                                                                                                          60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                                                                                                          Case Study 3 ndash Presentation

                                                                                                                                                                                                          TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                                                                                          PT 228 sec 113 ndash 146 sec

                                                                                                                                                                                                          APTT 45 sec 25 ndash 34 sec

                                                                                                                                                                                                          D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                                                                                          Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                                                                                          FV Normal 70-120

                                                                                                                                                                                                          FVII Normal 55-170

                                                                                                                                                                                                          FVIII Normal 60-150

                                                                                                                                                                                                          Protein C Normal 70-130

                                                                                                                                                                                                          Hb 134 gdL 14-16 gdL

                                                                                                                                                                                                          WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                                          ALT 32 IUL 0ndash34 IUL

                                                                                                                                                                                                          AST 28 IUL 0ndash34 IUL

                                                                                                                                                                                                          BUN 09 mgdL 08-13 mgdL

                                                                                                                                                                                                          Case Study 3 ndash Lab Results

                                                                                                                                                                                                          Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                                                                                          Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                                                                                          Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                                                                                          Case Study 4 ndash Presentation

                                                                                                                                                                                                          TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                                                                                          PT 28 sec 113 ndash 146 sec

                                                                                                                                                                                                          APTT 71 sec 25 ndash 34 sec

                                                                                                                                                                                                          D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                                                                                          Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                                                                                          FV Normal 70-120

                                                                                                                                                                                                          FVII Normal 55-170

                                                                                                                                                                                                          FVIII Normal 60-150

                                                                                                                                                                                                          Protein C Normal 70-130

                                                                                                                                                                                                          Hb 158 gdL 14-16 gdL

                                                                                                                                                                                                          WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                                          ALT 60 IUL 0ndash34 IUL

                                                                                                                                                                                                          AST 47 IUL 0ndash34 IUL

                                                                                                                                                                                                          BUN 38 mgdL 08-13 mgdL

                                                                                                                                                                                                          Case Study 4 ndash Lab Results

                                                                                                                                                                                                          Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                                                                                          Case Study 4 ndash Diagnosis

                                                                                                                                                                                                          55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                                                                                          Case Study 5 ndash Presentation

                                                                                                                                                                                                          Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                          Case Study 5 ndash Lab Results and Time Course

                                                                                                                                                                                                          Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                          TEST RESULT REFERENCE RANGE

                                                                                                                                                                                                          Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                                                                                          PT 215 sec 103 ndash 128 sec

                                                                                                                                                                                                          APTT 44 sec 26 ndash 36 sec

                                                                                                                                                                                                          D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                                                                                          Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                                                                                          FII FV FVIII Low Not reported (NR)

                                                                                                                                                                                                          FVII FIX FX vWF Normal NR

                                                                                                                                                                                                          Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                                                                                          DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                                                                                          dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                                                                                          (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                                                                                          (D) Illustration demonstrating repair

                                                                                                                                                                                                          Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                                                                                          Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                          29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                                                                          Case Study 6 ndash Presentation

                                                                                                                                                                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                          Case Study 6 ndash Lab Results

                                                                                                                                                                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                          TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                                                                          PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                                                                          INR 658 1 ndash 125

                                                                                                                                                                                                          APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                                                                          D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                                                                          Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                                                                          Albumin 28 gdL NR

                                                                                                                                                                                                          Hb 58 gdL NR

                                                                                                                                                                                                          LDH 1196 UL NR

                                                                                                                                                                                                          SGPT 144 IU NR

                                                                                                                                                                                                          SGOT 88 IU NR

                                                                                                                                                                                                          Bilirubin 32 mgdL NR

                                                                                                                                                                                                          DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                                                                          day postop

                                                                                                                                                                                                          Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                          HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                                                                          Case Study 6 ndash Discussion

                                                                                                                                                                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                          44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                                                                          Case Study 7 ndash Presentation

                                                                                                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                          On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                                                                          Case Study 7 ndash Presentation

                                                                                                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                          Case Study 7 ndash Lab Results vs Time

                                                                                                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                          Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                                                                          Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                          On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                                                          Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                          DIC Take Home Messages

                                                                                                                                                                                                          Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                                                          Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                                                          DIC

                                                                                                                                                                                                          Thank you Questions

                                                                                                                                                                                                          • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                                                          • Learning Objectives
                                                                                                                                                                                                          • Slide Number 3
                                                                                                                                                                                                          • Slide Number 4
                                                                                                                                                                                                          • Slide Number 5
                                                                                                                                                                                                          • Slide Number 6
                                                                                                                                                                                                          • Slide Number 7
                                                                                                                                                                                                          • Slide Number 8
                                                                                                                                                                                                          • Wound Sealing
                                                                                                                                                                                                          • The Three Steps of Hemostasis
                                                                                                                                                                                                          • Vessel Wall
                                                                                                                                                                                                          • Slide Number 12
                                                                                                                                                                                                          • Slide Number 13
                                                                                                                                                                                                          • Platelet Structure UnactivatedActivated
                                                                                                                                                                                                          • Primary Hemostasis
                                                                                                                                                                                                          • Primary Hemostasis Assays
                                                                                                                                                                                                          • Slide Number 17
                                                                                                                                                                                                          • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                                                          • Slide Number 19
                                                                                                                                                                                                          • Coagulation factors
                                                                                                                                                                                                          • Coagulation Assay Mechanisms
                                                                                                                                                                                                          • Slide Number 22
                                                                                                                                                                                                          • Fibrin Formation
                                                                                                                                                                                                          • Slide Number 24
                                                                                                                                                                                                          • Fibrinolysis Overview
                                                                                                                                                                                                          • Fibrinolysis Overview
                                                                                                                                                                                                          • Slide Number 27
                                                                                                                                                                                                          • Fibrinolysis Releases D-dimers
                                                                                                                                                                                                          • Basic Pathophysiology of DIC
                                                                                                                                                                                                          • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                                                          • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                                                          • Clinical Conditions Associated With DIC
                                                                                                                                                                                                          • Frequency of DIC in Selected Disease States
                                                                                                                                                                                                          • Underlying Diseases in DIC Patients
                                                                                                                                                                                                          • Slide Number 36
                                                                                                                                                                                                          • Slide Number 37
                                                                                                                                                                                                          • Slide Number 38
                                                                                                                                                                                                          • Slide Number 39
                                                                                                                                                                                                          • Pathophysiology of DIC
                                                                                                                                                                                                          • Pathogenesis of DIC in Sepsis
                                                                                                                                                                                                          • Host Response in Severe Sepsis
                                                                                                                                                                                                          • Organ Failure in Severe Sepsis
                                                                                                                                                                                                          • Mechanism of DIC in Organ Failure
                                                                                                                                                                                                          • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                                                          • Slide Number 47
                                                                                                                                                                                                          • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                                                          • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                                                          • Mechanism of DIC
                                                                                                                                                                                                          • Pathophysiology of DIC
                                                                                                                                                                                                          • Pathophysiology of DIC - Mechanism
                                                                                                                                                                                                          • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                                                          • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                                                          • Pathophysiology of Overt DIC
                                                                                                                                                                                                          • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                                                          • Slide Number 57
                                                                                                                                                                                                          • Slide Number 58
                                                                                                                                                                                                          • Slide Number 59
                                                                                                                                                                                                          • Slide Number 60
                                                                                                                                                                                                          • Slide Number 61
                                                                                                                                                                                                          • BREAK
                                                                                                                                                                                                          • Diagnostic and Management Approach for DIC
                                                                                                                                                                                                          • Diagnosis of DIC
                                                                                                                                                                                                          • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                                                          • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                                                          • Slide Number 67
                                                                                                                                                                                                          • Slide Number 68
                                                                                                                                                                                                          • British Journal of Haematology Overt DIC Score
                                                                                                                                                                                                          • Slide Number 70
                                                                                                                                                                                                          • Slide Number 71
                                                                                                                                                                                                          • Slide Number 72
                                                                                                                                                                                                          • Slide Number 73
                                                                                                                                                                                                          • DIC Management Goals
                                                                                                                                                                                                          • DIC Management and Treatment
                                                                                                                                                                                                          • DIC Management Strategies
                                                                                                                                                                                                          • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                                                          • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                                                          • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                                                          • D-dimer FDPs and DIC
                                                                                                                                                                                                          • D-Dimer and FDPs in DIC
                                                                                                                                                                                                          • Follow Up of DIC State of Disease
                                                                                                                                                                                                          • FMD-Dimer in DIC Major Differences
                                                                                                                                                                                                          • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                                                          • Slide Number 85
                                                                                                                                                                                                          • Slide Number 86
                                                                                                                                                                                                          • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                                                          • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                          • Slide Number 94
                                                                                                                                                                                                          • Slide Number 95
                                                                                                                                                                                                          • Slide Number 96
                                                                                                                                                                                                          • Slide Number 97
                                                                                                                                                                                                          • Slide Number 98
                                                                                                                                                                                                          • Slide Number 99
                                                                                                                                                                                                          • DIC Case Studies
                                                                                                                                                                                                          • Case Study 1 - Presentation
                                                                                                                                                                                                          • Case Study 1 ndash Lab Results
                                                                                                                                                                                                          • Case Study 1 ndash Microscopy
                                                                                                                                                                                                          • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                                                          • Slide Number 105
                                                                                                                                                                                                          • Slide Number 106
                                                                                                                                                                                                          • Slide Number 107
                                                                                                                                                                                                          • Slide Number 108
                                                                                                                                                                                                          • Slide Number 109
                                                                                                                                                                                                          • Slide Number 110
                                                                                                                                                                                                          • Slide Number 111
                                                                                                                                                                                                          • Slide Number 112
                                                                                                                                                                                                          • Slide Number 113
                                                                                                                                                                                                          • Slide Number 114
                                                                                                                                                                                                          • Slide Number 115
                                                                                                                                                                                                          • Slide Number 116
                                                                                                                                                                                                          • Slide Number 117
                                                                                                                                                                                                          • Slide Number 118
                                                                                                                                                                                                          • Slide Number 119
                                                                                                                                                                                                          • Slide Number 120
                                                                                                                                                                                                          • Slide Number 121
                                                                                                                                                                                                          • Slide Number 122
                                                                                                                                                                                                          • Slide Number 123
                                                                                                                                                                                                          • Slide Number 124
                                                                                                                                                                                                          • Slide Number 125
                                                                                                                                                                                                          • DIC Take Home Messages
                                                                                                                                                                                                          • Slide Number 127
                                                                                                                                                                                                          • Slide Number 128

                                                                                                                                                                                                            Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE

                                                                                                                                                                                                            WBC count 77 KμL 423 ndash 907 x KμL

                                                                                                                                                                                                            RBC count 17 MμL 137 ndash 175 x MμL

                                                                                                                                                                                                            Hemoglobin 67 gdL 137 ndash 175 gdL

                                                                                                                                                                                                            Hematocrit 195 401 ndash 510

                                                                                                                                                                                                            MCV 95 fL 790 ndash 922 fL

                                                                                                                                                                                                            MPV 12 fL 94 ndash 124 fL

                                                                                                                                                                                                            Platelet count 9 KμL 161 ndash 347 KμL

                                                                                                                                                                                                            Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0

                                                                                                                                                                                                            Lymphocytes monocytes eosinophils basophils all below normal range

                                                                                                                                                                                                            PT 47 sec (corrected on mixing study) 116 ndash 152 sec

                                                                                                                                                                                                            APTT 75 sec (corrected on mixing study) 253 ndash 373 sec

                                                                                                                                                                                                            Fibrinogen lt 76 mgdL 177 ndash 466 mgdL

                                                                                                                                                                                                            D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU

                                                                                                                                                                                                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                                            Case Study 1 ndash Microscopy

                                                                                                                                                                                                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                                            Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                                                                                                            Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                                                                                                            DIC due to TF release by APL blasts

                                                                                                                                                                                                            Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                                                                                                            Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                                                                                                            Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                                            20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                                                                                                            Case Study 2 ndash Presentation

                                                                                                                                                                                                            TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                                                                                                            PT 30 sec 113 ndash 146 sec

                                                                                                                                                                                                            APTT 75 sec 25 ndash 34 sec

                                                                                                                                                                                                            D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                                                                                                            Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                                                                                                            pH 728 738 to 742

                                                                                                                                                                                                            PaO2 570 mmHg 80-100 mmHg

                                                                                                                                                                                                            WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                                            ALT 111 IUL 0ndash34 IUL

                                                                                                                                                                                                            AST 61 IUL 0ndash34 IUL

                                                                                                                                                                                                            BUN 303 mgdL 08-13 mgdL

                                                                                                                                                                                                            Case Study 2 ndash Lab Results

                                                                                                                                                                                                            Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                                                                                                            Case Study 2 ndash Diagnosis

                                                                                                                                                                                                            60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                                                                                                            Case Study 3 ndash Presentation

                                                                                                                                                                                                            TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                                                                                            PT 228 sec 113 ndash 146 sec

                                                                                                                                                                                                            APTT 45 sec 25 ndash 34 sec

                                                                                                                                                                                                            D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                                                                                            Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                                                                                            FV Normal 70-120

                                                                                                                                                                                                            FVII Normal 55-170

                                                                                                                                                                                                            FVIII Normal 60-150

                                                                                                                                                                                                            Protein C Normal 70-130

                                                                                                                                                                                                            Hb 134 gdL 14-16 gdL

                                                                                                                                                                                                            WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                                            ALT 32 IUL 0ndash34 IUL

                                                                                                                                                                                                            AST 28 IUL 0ndash34 IUL

                                                                                                                                                                                                            BUN 09 mgdL 08-13 mgdL

                                                                                                                                                                                                            Case Study 3 ndash Lab Results

                                                                                                                                                                                                            Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                                                                                            Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                                                                                            Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                                                                                            Case Study 4 ndash Presentation

                                                                                                                                                                                                            TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                                                                                            PT 28 sec 113 ndash 146 sec

                                                                                                                                                                                                            APTT 71 sec 25 ndash 34 sec

                                                                                                                                                                                                            D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                                                                                            Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                                                                                            FV Normal 70-120

                                                                                                                                                                                                            FVII Normal 55-170

                                                                                                                                                                                                            FVIII Normal 60-150

                                                                                                                                                                                                            Protein C Normal 70-130

                                                                                                                                                                                                            Hb 158 gdL 14-16 gdL

                                                                                                                                                                                                            WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                                            ALT 60 IUL 0ndash34 IUL

                                                                                                                                                                                                            AST 47 IUL 0ndash34 IUL

                                                                                                                                                                                                            BUN 38 mgdL 08-13 mgdL

                                                                                                                                                                                                            Case Study 4 ndash Lab Results

                                                                                                                                                                                                            Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                                                                                            Case Study 4 ndash Diagnosis

                                                                                                                                                                                                            55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                                                                                            Case Study 5 ndash Presentation

                                                                                                                                                                                                            Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                            Case Study 5 ndash Lab Results and Time Course

                                                                                                                                                                                                            Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                            TEST RESULT REFERENCE RANGE

                                                                                                                                                                                                            Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                                                                                            PT 215 sec 103 ndash 128 sec

                                                                                                                                                                                                            APTT 44 sec 26 ndash 36 sec

                                                                                                                                                                                                            D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                                                                                            Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                                                                                            FII FV FVIII Low Not reported (NR)

                                                                                                                                                                                                            FVII FIX FX vWF Normal NR

                                                                                                                                                                                                            Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                                                                                            DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                                                                                            dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                                                                                            (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                                                                                            (D) Illustration demonstrating repair

                                                                                                                                                                                                            Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                                                                                            Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                            29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                                                                            Case Study 6 ndash Presentation

                                                                                                                                                                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                            Case Study 6 ndash Lab Results

                                                                                                                                                                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                            TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                                                                            PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                                                                            INR 658 1 ndash 125

                                                                                                                                                                                                            APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                                                                            D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                                                                            Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                                                                            Albumin 28 gdL NR

                                                                                                                                                                                                            Hb 58 gdL NR

                                                                                                                                                                                                            LDH 1196 UL NR

                                                                                                                                                                                                            SGPT 144 IU NR

                                                                                                                                                                                                            SGOT 88 IU NR

                                                                                                                                                                                                            Bilirubin 32 mgdL NR

                                                                                                                                                                                                            DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                                                                            day postop

                                                                                                                                                                                                            Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                            HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                                                                            Case Study 6 ndash Discussion

                                                                                                                                                                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                            44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                                                                            Case Study 7 ndash Presentation

                                                                                                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                            On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                                                                            Case Study 7 ndash Presentation

                                                                                                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                            Case Study 7 ndash Lab Results vs Time

                                                                                                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                            Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                                                                            Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                            On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                                                            Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                            DIC Take Home Messages

                                                                                                                                                                                                            Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                                                            Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                                                            DIC

                                                                                                                                                                                                            Thank you Questions

                                                                                                                                                                                                            • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                                                            • Learning Objectives
                                                                                                                                                                                                            • Slide Number 3
                                                                                                                                                                                                            • Slide Number 4
                                                                                                                                                                                                            • Slide Number 5
                                                                                                                                                                                                            • Slide Number 6
                                                                                                                                                                                                            • Slide Number 7
                                                                                                                                                                                                            • Slide Number 8
                                                                                                                                                                                                            • Wound Sealing
                                                                                                                                                                                                            • The Three Steps of Hemostasis
                                                                                                                                                                                                            • Vessel Wall
                                                                                                                                                                                                            • Slide Number 12
                                                                                                                                                                                                            • Slide Number 13
                                                                                                                                                                                                            • Platelet Structure UnactivatedActivated
                                                                                                                                                                                                            • Primary Hemostasis
                                                                                                                                                                                                            • Primary Hemostasis Assays
                                                                                                                                                                                                            • Slide Number 17
                                                                                                                                                                                                            • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                                                            • Slide Number 19
                                                                                                                                                                                                            • Coagulation factors
                                                                                                                                                                                                            • Coagulation Assay Mechanisms
                                                                                                                                                                                                            • Slide Number 22
                                                                                                                                                                                                            • Fibrin Formation
                                                                                                                                                                                                            • Slide Number 24
                                                                                                                                                                                                            • Fibrinolysis Overview
                                                                                                                                                                                                            • Fibrinolysis Overview
                                                                                                                                                                                                            • Slide Number 27
                                                                                                                                                                                                            • Fibrinolysis Releases D-dimers
                                                                                                                                                                                                            • Basic Pathophysiology of DIC
                                                                                                                                                                                                            • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                                                            • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                                                            • Clinical Conditions Associated With DIC
                                                                                                                                                                                                            • Frequency of DIC in Selected Disease States
                                                                                                                                                                                                            • Underlying Diseases in DIC Patients
                                                                                                                                                                                                            • Slide Number 36
                                                                                                                                                                                                            • Slide Number 37
                                                                                                                                                                                                            • Slide Number 38
                                                                                                                                                                                                            • Slide Number 39
                                                                                                                                                                                                            • Pathophysiology of DIC
                                                                                                                                                                                                            • Pathogenesis of DIC in Sepsis
                                                                                                                                                                                                            • Host Response in Severe Sepsis
                                                                                                                                                                                                            • Organ Failure in Severe Sepsis
                                                                                                                                                                                                            • Mechanism of DIC in Organ Failure
                                                                                                                                                                                                            • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                                                            • Slide Number 47
                                                                                                                                                                                                            • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                                                            • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                                                            • Mechanism of DIC
                                                                                                                                                                                                            • Pathophysiology of DIC
                                                                                                                                                                                                            • Pathophysiology of DIC - Mechanism
                                                                                                                                                                                                            • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                                                            • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                                                            • Pathophysiology of Overt DIC
                                                                                                                                                                                                            • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                                                            • Slide Number 57
                                                                                                                                                                                                            • Slide Number 58
                                                                                                                                                                                                            • Slide Number 59
                                                                                                                                                                                                            • Slide Number 60
                                                                                                                                                                                                            • Slide Number 61
                                                                                                                                                                                                            • BREAK
                                                                                                                                                                                                            • Diagnostic and Management Approach for DIC
                                                                                                                                                                                                            • Diagnosis of DIC
                                                                                                                                                                                                            • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                                                            • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                                                            • Slide Number 67
                                                                                                                                                                                                            • Slide Number 68
                                                                                                                                                                                                            • British Journal of Haematology Overt DIC Score
                                                                                                                                                                                                            • Slide Number 70
                                                                                                                                                                                                            • Slide Number 71
                                                                                                                                                                                                            • Slide Number 72
                                                                                                                                                                                                            • Slide Number 73
                                                                                                                                                                                                            • DIC Management Goals
                                                                                                                                                                                                            • DIC Management and Treatment
                                                                                                                                                                                                            • DIC Management Strategies
                                                                                                                                                                                                            • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                                                            • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                                                            • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                                                            • D-dimer FDPs and DIC
                                                                                                                                                                                                            • D-Dimer and FDPs in DIC
                                                                                                                                                                                                            • Follow Up of DIC State of Disease
                                                                                                                                                                                                            • FMD-Dimer in DIC Major Differences
                                                                                                                                                                                                            • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                                                            • Slide Number 85
                                                                                                                                                                                                            • Slide Number 86
                                                                                                                                                                                                            • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                                                            • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                            • Slide Number 94
                                                                                                                                                                                                            • Slide Number 95
                                                                                                                                                                                                            • Slide Number 96
                                                                                                                                                                                                            • Slide Number 97
                                                                                                                                                                                                            • Slide Number 98
                                                                                                                                                                                                            • Slide Number 99
                                                                                                                                                                                                            • DIC Case Studies
                                                                                                                                                                                                            • Case Study 1 - Presentation
                                                                                                                                                                                                            • Case Study 1 ndash Lab Results
                                                                                                                                                                                                            • Case Study 1 ndash Microscopy
                                                                                                                                                                                                            • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                                                            • Slide Number 105
                                                                                                                                                                                                            • Slide Number 106
                                                                                                                                                                                                            • Slide Number 107
                                                                                                                                                                                                            • Slide Number 108
                                                                                                                                                                                                            • Slide Number 109
                                                                                                                                                                                                            • Slide Number 110
                                                                                                                                                                                                            • Slide Number 111
                                                                                                                                                                                                            • Slide Number 112
                                                                                                                                                                                                            • Slide Number 113
                                                                                                                                                                                                            • Slide Number 114
                                                                                                                                                                                                            • Slide Number 115
                                                                                                                                                                                                            • Slide Number 116
                                                                                                                                                                                                            • Slide Number 117
                                                                                                                                                                                                            • Slide Number 118
                                                                                                                                                                                                            • Slide Number 119
                                                                                                                                                                                                            • Slide Number 120
                                                                                                                                                                                                            • Slide Number 121
                                                                                                                                                                                                            • Slide Number 122
                                                                                                                                                                                                            • Slide Number 123
                                                                                                                                                                                                            • Slide Number 124
                                                                                                                                                                                                            • Slide Number 125
                                                                                                                                                                                                            • DIC Take Home Messages
                                                                                                                                                                                                            • Slide Number 127
                                                                                                                                                                                                            • Slide Number 128

                                                                                                                                                                                                              Case Study 1 ndash Microscopy

                                                                                                                                                                                                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                                              Arrow shows giant platelets in this peripheral smear Promyelocytes apparent

                                                                                                                                                                                                              Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                                                                                                              DIC due to TF release by APL blasts

                                                                                                                                                                                                              Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                                                                                                              Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                                                                                                              Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                                              20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                                                                                                              Case Study 2 ndash Presentation

                                                                                                                                                                                                              TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                                                                                                              PT 30 sec 113 ndash 146 sec

                                                                                                                                                                                                              APTT 75 sec 25 ndash 34 sec

                                                                                                                                                                                                              D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                                                                                                              Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                                                                                                              pH 728 738 to 742

                                                                                                                                                                                                              PaO2 570 mmHg 80-100 mmHg

                                                                                                                                                                                                              WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                                              ALT 111 IUL 0ndash34 IUL

                                                                                                                                                                                                              AST 61 IUL 0ndash34 IUL

                                                                                                                                                                                                              BUN 303 mgdL 08-13 mgdL

                                                                                                                                                                                                              Case Study 2 ndash Lab Results

                                                                                                                                                                                                              Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                                                                                                              Case Study 2 ndash Diagnosis

                                                                                                                                                                                                              60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                                                                                                              Case Study 3 ndash Presentation

                                                                                                                                                                                                              TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                                                                                              PT 228 sec 113 ndash 146 sec

                                                                                                                                                                                                              APTT 45 sec 25 ndash 34 sec

                                                                                                                                                                                                              D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                                                                                              Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                                                                                              FV Normal 70-120

                                                                                                                                                                                                              FVII Normal 55-170

                                                                                                                                                                                                              FVIII Normal 60-150

                                                                                                                                                                                                              Protein C Normal 70-130

                                                                                                                                                                                                              Hb 134 gdL 14-16 gdL

                                                                                                                                                                                                              WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                                              ALT 32 IUL 0ndash34 IUL

                                                                                                                                                                                                              AST 28 IUL 0ndash34 IUL

                                                                                                                                                                                                              BUN 09 mgdL 08-13 mgdL

                                                                                                                                                                                                              Case Study 3 ndash Lab Results

                                                                                                                                                                                                              Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                                                                                              Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                                                                                              Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                                                                                              Case Study 4 ndash Presentation

                                                                                                                                                                                                              TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                                                                                              PT 28 sec 113 ndash 146 sec

                                                                                                                                                                                                              APTT 71 sec 25 ndash 34 sec

                                                                                                                                                                                                              D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                                                                                              Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                                                                                              FV Normal 70-120

                                                                                                                                                                                                              FVII Normal 55-170

                                                                                                                                                                                                              FVIII Normal 60-150

                                                                                                                                                                                                              Protein C Normal 70-130

                                                                                                                                                                                                              Hb 158 gdL 14-16 gdL

                                                                                                                                                                                                              WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                                              ALT 60 IUL 0ndash34 IUL

                                                                                                                                                                                                              AST 47 IUL 0ndash34 IUL

                                                                                                                                                                                                              BUN 38 mgdL 08-13 mgdL

                                                                                                                                                                                                              Case Study 4 ndash Lab Results

                                                                                                                                                                                                              Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                                                                                              Case Study 4 ndash Diagnosis

                                                                                                                                                                                                              55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                                                                                              Case Study 5 ndash Presentation

                                                                                                                                                                                                              Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                              Case Study 5 ndash Lab Results and Time Course

                                                                                                                                                                                                              Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                              TEST RESULT REFERENCE RANGE

                                                                                                                                                                                                              Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                                                                                              PT 215 sec 103 ndash 128 sec

                                                                                                                                                                                                              APTT 44 sec 26 ndash 36 sec

                                                                                                                                                                                                              D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                                                                                              Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                                                                                              FII FV FVIII Low Not reported (NR)

                                                                                                                                                                                                              FVII FIX FX vWF Normal NR

                                                                                                                                                                                                              Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                                                                                              DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                                                                                              dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                                                                                              (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                                                                                              (D) Illustration demonstrating repair

                                                                                                                                                                                                              Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                                                                                              Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                              29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                                                                              Case Study 6 ndash Presentation

                                                                                                                                                                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                              Case Study 6 ndash Lab Results

                                                                                                                                                                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                              TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                                                                              PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                                                                              INR 658 1 ndash 125

                                                                                                                                                                                                              APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                                                                              D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                                                                              Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                                                                              Albumin 28 gdL NR

                                                                                                                                                                                                              Hb 58 gdL NR

                                                                                                                                                                                                              LDH 1196 UL NR

                                                                                                                                                                                                              SGPT 144 IU NR

                                                                                                                                                                                                              SGOT 88 IU NR

                                                                                                                                                                                                              Bilirubin 32 mgdL NR

                                                                                                                                                                                                              DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                                                                              day postop

                                                                                                                                                                                                              Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                              HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                                                                              Case Study 6 ndash Discussion

                                                                                                                                                                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                              44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                                                                              Case Study 7 ndash Presentation

                                                                                                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                              On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                                                                              Case Study 7 ndash Presentation

                                                                                                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                              Case Study 7 ndash Lab Results vs Time

                                                                                                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                              Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                                                                              Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                              On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                                                              Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                              DIC Take Home Messages

                                                                                                                                                                                                              Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                                                              Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                                                              DIC

                                                                                                                                                                                                              Thank you Questions

                                                                                                                                                                                                              • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                                                              • Learning Objectives
                                                                                                                                                                                                              • Slide Number 3
                                                                                                                                                                                                              • Slide Number 4
                                                                                                                                                                                                              • Slide Number 5
                                                                                                                                                                                                              • Slide Number 6
                                                                                                                                                                                                              • Slide Number 7
                                                                                                                                                                                                              • Slide Number 8
                                                                                                                                                                                                              • Wound Sealing
                                                                                                                                                                                                              • The Three Steps of Hemostasis
                                                                                                                                                                                                              • Vessel Wall
                                                                                                                                                                                                              • Slide Number 12
                                                                                                                                                                                                              • Slide Number 13
                                                                                                                                                                                                              • Platelet Structure UnactivatedActivated
                                                                                                                                                                                                              • Primary Hemostasis
                                                                                                                                                                                                              • Primary Hemostasis Assays
                                                                                                                                                                                                              • Slide Number 17
                                                                                                                                                                                                              • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                                                              • Slide Number 19
                                                                                                                                                                                                              • Coagulation factors
                                                                                                                                                                                                              • Coagulation Assay Mechanisms
                                                                                                                                                                                                              • Slide Number 22
                                                                                                                                                                                                              • Fibrin Formation
                                                                                                                                                                                                              • Slide Number 24
                                                                                                                                                                                                              • Fibrinolysis Overview
                                                                                                                                                                                                              • Fibrinolysis Overview
                                                                                                                                                                                                              • Slide Number 27
                                                                                                                                                                                                              • Fibrinolysis Releases D-dimers
                                                                                                                                                                                                              • Basic Pathophysiology of DIC
                                                                                                                                                                                                              • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                                                              • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                                                              • Clinical Conditions Associated With DIC
                                                                                                                                                                                                              • Frequency of DIC in Selected Disease States
                                                                                                                                                                                                              • Underlying Diseases in DIC Patients
                                                                                                                                                                                                              • Slide Number 36
                                                                                                                                                                                                              • Slide Number 37
                                                                                                                                                                                                              • Slide Number 38
                                                                                                                                                                                                              • Slide Number 39
                                                                                                                                                                                                              • Pathophysiology of DIC
                                                                                                                                                                                                              • Pathogenesis of DIC in Sepsis
                                                                                                                                                                                                              • Host Response in Severe Sepsis
                                                                                                                                                                                                              • Organ Failure in Severe Sepsis
                                                                                                                                                                                                              • Mechanism of DIC in Organ Failure
                                                                                                                                                                                                              • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                                                              • Slide Number 47
                                                                                                                                                                                                              • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                                                              • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                                                              • Mechanism of DIC
                                                                                                                                                                                                              • Pathophysiology of DIC
                                                                                                                                                                                                              • Pathophysiology of DIC - Mechanism
                                                                                                                                                                                                              • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                                                              • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                                                              • Pathophysiology of Overt DIC
                                                                                                                                                                                                              • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                                                              • Slide Number 57
                                                                                                                                                                                                              • Slide Number 58
                                                                                                                                                                                                              • Slide Number 59
                                                                                                                                                                                                              • Slide Number 60
                                                                                                                                                                                                              • Slide Number 61
                                                                                                                                                                                                              • BREAK
                                                                                                                                                                                                              • Diagnostic and Management Approach for DIC
                                                                                                                                                                                                              • Diagnosis of DIC
                                                                                                                                                                                                              • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                                                              • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                                                              • Slide Number 67
                                                                                                                                                                                                              • Slide Number 68
                                                                                                                                                                                                              • British Journal of Haematology Overt DIC Score
                                                                                                                                                                                                              • Slide Number 70
                                                                                                                                                                                                              • Slide Number 71
                                                                                                                                                                                                              • Slide Number 72
                                                                                                                                                                                                              • Slide Number 73
                                                                                                                                                                                                              • DIC Management Goals
                                                                                                                                                                                                              • DIC Management and Treatment
                                                                                                                                                                                                              • DIC Management Strategies
                                                                                                                                                                                                              • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                                                              • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                                                              • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                                                              • D-dimer FDPs and DIC
                                                                                                                                                                                                              • D-Dimer and FDPs in DIC
                                                                                                                                                                                                              • Follow Up of DIC State of Disease
                                                                                                                                                                                                              • FMD-Dimer in DIC Major Differences
                                                                                                                                                                                                              • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                                                              • Slide Number 85
                                                                                                                                                                                                              • Slide Number 86
                                                                                                                                                                                                              • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                                                              • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                              • Slide Number 94
                                                                                                                                                                                                              • Slide Number 95
                                                                                                                                                                                                              • Slide Number 96
                                                                                                                                                                                                              • Slide Number 97
                                                                                                                                                                                                              • Slide Number 98
                                                                                                                                                                                                              • Slide Number 99
                                                                                                                                                                                                              • DIC Case Studies
                                                                                                                                                                                                              • Case Study 1 - Presentation
                                                                                                                                                                                                              • Case Study 1 ndash Lab Results
                                                                                                                                                                                                              • Case Study 1 ndash Microscopy
                                                                                                                                                                                                              • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                                                              • Slide Number 105
                                                                                                                                                                                                              • Slide Number 106
                                                                                                                                                                                                              • Slide Number 107
                                                                                                                                                                                                              • Slide Number 108
                                                                                                                                                                                                              • Slide Number 109
                                                                                                                                                                                                              • Slide Number 110
                                                                                                                                                                                                              • Slide Number 111
                                                                                                                                                                                                              • Slide Number 112
                                                                                                                                                                                                              • Slide Number 113
                                                                                                                                                                                                              • Slide Number 114
                                                                                                                                                                                                              • Slide Number 115
                                                                                                                                                                                                              • Slide Number 116
                                                                                                                                                                                                              • Slide Number 117
                                                                                                                                                                                                              • Slide Number 118
                                                                                                                                                                                                              • Slide Number 119
                                                                                                                                                                                                              • Slide Number 120
                                                                                                                                                                                                              • Slide Number 121
                                                                                                                                                                                                              • Slide Number 122
                                                                                                                                                                                                              • Slide Number 123
                                                                                                                                                                                                              • Slide Number 124
                                                                                                                                                                                                              • Slide Number 125
                                                                                                                                                                                                              • DIC Take Home Messages
                                                                                                                                                                                                              • Slide Number 127
                                                                                                                                                                                                              • Slide Number 128

                                                                                                                                                                                                                Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)

                                                                                                                                                                                                                DIC due to TF release by APL blasts

                                                                                                                                                                                                                Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases

                                                                                                                                                                                                                Transfusions to replace factors along with platelets and RBCs during APL treatment

                                                                                                                                                                                                                Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14

                                                                                                                                                                                                                20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                                                                                                                Case Study 2 ndash Presentation

                                                                                                                                                                                                                TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                                                                                                                PT 30 sec 113 ndash 146 sec

                                                                                                                                                                                                                APTT 75 sec 25 ndash 34 sec

                                                                                                                                                                                                                D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                                                                                                                Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                                                                                                                pH 728 738 to 742

                                                                                                                                                                                                                PaO2 570 mmHg 80-100 mmHg

                                                                                                                                                                                                                WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                                                ALT 111 IUL 0ndash34 IUL

                                                                                                                                                                                                                AST 61 IUL 0ndash34 IUL

                                                                                                                                                                                                                BUN 303 mgdL 08-13 mgdL

                                                                                                                                                                                                                Case Study 2 ndash Lab Results

                                                                                                                                                                                                                Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                                                                                                                Case Study 2 ndash Diagnosis

                                                                                                                                                                                                                60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                                                                                                                Case Study 3 ndash Presentation

                                                                                                                                                                                                                TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                                                                                                PT 228 sec 113 ndash 146 sec

                                                                                                                                                                                                                APTT 45 sec 25 ndash 34 sec

                                                                                                                                                                                                                D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                                                                                                Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                                                                                                FV Normal 70-120

                                                                                                                                                                                                                FVII Normal 55-170

                                                                                                                                                                                                                FVIII Normal 60-150

                                                                                                                                                                                                                Protein C Normal 70-130

                                                                                                                                                                                                                Hb 134 gdL 14-16 gdL

                                                                                                                                                                                                                WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                                                ALT 32 IUL 0ndash34 IUL

                                                                                                                                                                                                                AST 28 IUL 0ndash34 IUL

                                                                                                                                                                                                                BUN 09 mgdL 08-13 mgdL

                                                                                                                                                                                                                Case Study 3 ndash Lab Results

                                                                                                                                                                                                                Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                                                                                                Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                                                                                                Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                                                                                                Case Study 4 ndash Presentation

                                                                                                                                                                                                                TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                                                                                                PT 28 sec 113 ndash 146 sec

                                                                                                                                                                                                                APTT 71 sec 25 ndash 34 sec

                                                                                                                                                                                                                D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                                                                                                Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                                                                                                FV Normal 70-120

                                                                                                                                                                                                                FVII Normal 55-170

                                                                                                                                                                                                                FVIII Normal 60-150

                                                                                                                                                                                                                Protein C Normal 70-130

                                                                                                                                                                                                                Hb 158 gdL 14-16 gdL

                                                                                                                                                                                                                WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                                                ALT 60 IUL 0ndash34 IUL

                                                                                                                                                                                                                AST 47 IUL 0ndash34 IUL

                                                                                                                                                                                                                BUN 38 mgdL 08-13 mgdL

                                                                                                                                                                                                                Case Study 4 ndash Lab Results

                                                                                                                                                                                                                Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                                                                                                Case Study 4 ndash Diagnosis

                                                                                                                                                                                                                55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                                                                                                Case Study 5 ndash Presentation

                                                                                                                                                                                                                Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                                Case Study 5 ndash Lab Results and Time Course

                                                                                                                                                                                                                Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                                TEST RESULT REFERENCE RANGE

                                                                                                                                                                                                                Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                                                                                                PT 215 sec 103 ndash 128 sec

                                                                                                                                                                                                                APTT 44 sec 26 ndash 36 sec

                                                                                                                                                                                                                D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                                                                                                Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                                                                                                FII FV FVIII Low Not reported (NR)

                                                                                                                                                                                                                FVII FIX FX vWF Normal NR

                                                                                                                                                                                                                Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                                                                                                DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                                                                                                dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                                                                                                (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                                                                                                (D) Illustration demonstrating repair

                                                                                                                                                                                                                Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                                                                                                Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                                29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                                                                                Case Study 6 ndash Presentation

                                                                                                                                                                                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                Case Study 6 ndash Lab Results

                                                                                                                                                                                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                                                                                PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                                                                                INR 658 1 ndash 125

                                                                                                                                                                                                                APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                                                                                D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                                                                                Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                                                                                Albumin 28 gdL NR

                                                                                                                                                                                                                Hb 58 gdL NR

                                                                                                                                                                                                                LDH 1196 UL NR

                                                                                                                                                                                                                SGPT 144 IU NR

                                                                                                                                                                                                                SGOT 88 IU NR

                                                                                                                                                                                                                Bilirubin 32 mgdL NR

                                                                                                                                                                                                                DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                                                                                day postop

                                                                                                                                                                                                                Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                                                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                                                                                Case Study 6 ndash Discussion

                                                                                                                                                                                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                                                                                Case Study 7 ndash Presentation

                                                                                                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                                                                                Case Study 7 ndash Presentation

                                                                                                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                Case Study 7 ndash Lab Results vs Time

                                                                                                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                                                                                Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                                                                Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                DIC Take Home Messages

                                                                                                                                                                                                                Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                                                                Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                                                                DIC

                                                                                                                                                                                                                Thank you Questions

                                                                                                                                                                                                                • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                                                                • Learning Objectives
                                                                                                                                                                                                                • Slide Number 3
                                                                                                                                                                                                                • Slide Number 4
                                                                                                                                                                                                                • Slide Number 5
                                                                                                                                                                                                                • Slide Number 6
                                                                                                                                                                                                                • Slide Number 7
                                                                                                                                                                                                                • Slide Number 8
                                                                                                                                                                                                                • Wound Sealing
                                                                                                                                                                                                                • The Three Steps of Hemostasis
                                                                                                                                                                                                                • Vessel Wall
                                                                                                                                                                                                                • Slide Number 12
                                                                                                                                                                                                                • Slide Number 13
                                                                                                                                                                                                                • Platelet Structure UnactivatedActivated
                                                                                                                                                                                                                • Primary Hemostasis
                                                                                                                                                                                                                • Primary Hemostasis Assays
                                                                                                                                                                                                                • Slide Number 17
                                                                                                                                                                                                                • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                                                                • Slide Number 19
                                                                                                                                                                                                                • Coagulation factors
                                                                                                                                                                                                                • Coagulation Assay Mechanisms
                                                                                                                                                                                                                • Slide Number 22
                                                                                                                                                                                                                • Fibrin Formation
                                                                                                                                                                                                                • Slide Number 24
                                                                                                                                                                                                                • Fibrinolysis Overview
                                                                                                                                                                                                                • Fibrinolysis Overview
                                                                                                                                                                                                                • Slide Number 27
                                                                                                                                                                                                                • Fibrinolysis Releases D-dimers
                                                                                                                                                                                                                • Basic Pathophysiology of DIC
                                                                                                                                                                                                                • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                                                                • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                                                                • Clinical Conditions Associated With DIC
                                                                                                                                                                                                                • Frequency of DIC in Selected Disease States
                                                                                                                                                                                                                • Underlying Diseases in DIC Patients
                                                                                                                                                                                                                • Slide Number 36
                                                                                                                                                                                                                • Slide Number 37
                                                                                                                                                                                                                • Slide Number 38
                                                                                                                                                                                                                • Slide Number 39
                                                                                                                                                                                                                • Pathophysiology of DIC
                                                                                                                                                                                                                • Pathogenesis of DIC in Sepsis
                                                                                                                                                                                                                • Host Response in Severe Sepsis
                                                                                                                                                                                                                • Organ Failure in Severe Sepsis
                                                                                                                                                                                                                • Mechanism of DIC in Organ Failure
                                                                                                                                                                                                                • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                                                                • Slide Number 47
                                                                                                                                                                                                                • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                                                                • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                                                                • Mechanism of DIC
                                                                                                                                                                                                                • Pathophysiology of DIC
                                                                                                                                                                                                                • Pathophysiology of DIC - Mechanism
                                                                                                                                                                                                                • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                                                                • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                                                                • Pathophysiology of Overt DIC
                                                                                                                                                                                                                • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                                                                • Slide Number 57
                                                                                                                                                                                                                • Slide Number 58
                                                                                                                                                                                                                • Slide Number 59
                                                                                                                                                                                                                • Slide Number 60
                                                                                                                                                                                                                • Slide Number 61
                                                                                                                                                                                                                • BREAK
                                                                                                                                                                                                                • Diagnostic and Management Approach for DIC
                                                                                                                                                                                                                • Diagnosis of DIC
                                                                                                                                                                                                                • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                                                                • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                                                                • Slide Number 67
                                                                                                                                                                                                                • Slide Number 68
                                                                                                                                                                                                                • British Journal of Haematology Overt DIC Score
                                                                                                                                                                                                                • Slide Number 70
                                                                                                                                                                                                                • Slide Number 71
                                                                                                                                                                                                                • Slide Number 72
                                                                                                                                                                                                                • Slide Number 73
                                                                                                                                                                                                                • DIC Management Goals
                                                                                                                                                                                                                • DIC Management and Treatment
                                                                                                                                                                                                                • DIC Management Strategies
                                                                                                                                                                                                                • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                                                                • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                                                                • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                                                                • D-dimer FDPs and DIC
                                                                                                                                                                                                                • D-Dimer and FDPs in DIC
                                                                                                                                                                                                                • Follow Up of DIC State of Disease
                                                                                                                                                                                                                • FMD-Dimer in DIC Major Differences
                                                                                                                                                                                                                • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                                                                • Slide Number 85
                                                                                                                                                                                                                • Slide Number 86
                                                                                                                                                                                                                • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                                                                • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                • Slide Number 94
                                                                                                                                                                                                                • Slide Number 95
                                                                                                                                                                                                                • Slide Number 96
                                                                                                                                                                                                                • Slide Number 97
                                                                                                                                                                                                                • Slide Number 98
                                                                                                                                                                                                                • Slide Number 99
                                                                                                                                                                                                                • DIC Case Studies
                                                                                                                                                                                                                • Case Study 1 - Presentation
                                                                                                                                                                                                                • Case Study 1 ndash Lab Results
                                                                                                                                                                                                                • Case Study 1 ndash Microscopy
                                                                                                                                                                                                                • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                                                                • Slide Number 105
                                                                                                                                                                                                                • Slide Number 106
                                                                                                                                                                                                                • Slide Number 107
                                                                                                                                                                                                                • Slide Number 108
                                                                                                                                                                                                                • Slide Number 109
                                                                                                                                                                                                                • Slide Number 110
                                                                                                                                                                                                                • Slide Number 111
                                                                                                                                                                                                                • Slide Number 112
                                                                                                                                                                                                                • Slide Number 113
                                                                                                                                                                                                                • Slide Number 114
                                                                                                                                                                                                                • Slide Number 115
                                                                                                                                                                                                                • Slide Number 116
                                                                                                                                                                                                                • Slide Number 117
                                                                                                                                                                                                                • Slide Number 118
                                                                                                                                                                                                                • Slide Number 119
                                                                                                                                                                                                                • Slide Number 120
                                                                                                                                                                                                                • Slide Number 121
                                                                                                                                                                                                                • Slide Number 122
                                                                                                                                                                                                                • Slide Number 123
                                                                                                                                                                                                                • Slide Number 124
                                                                                                                                                                                                                • Slide Number 125
                                                                                                                                                                                                                • DIC Take Home Messages
                                                                                                                                                                                                                • Slide Number 127
                                                                                                                                                                                                                • Slide Number 128

                                                                                                                                                                                                                  20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started

                                                                                                                                                                                                                  Case Study 2 ndash Presentation

                                                                                                                                                                                                                  TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                                                                                                                  PT 30 sec 113 ndash 146 sec

                                                                                                                                                                                                                  APTT 75 sec 25 ndash 34 sec

                                                                                                                                                                                                                  D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                                                                                                                  Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                                                                                                                  pH 728 738 to 742

                                                                                                                                                                                                                  PaO2 570 mmHg 80-100 mmHg

                                                                                                                                                                                                                  WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                                                  ALT 111 IUL 0ndash34 IUL

                                                                                                                                                                                                                  AST 61 IUL 0ndash34 IUL

                                                                                                                                                                                                                  BUN 303 mgdL 08-13 mgdL

                                                                                                                                                                                                                  Case Study 2 ndash Lab Results

                                                                                                                                                                                                                  Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                                                                                                                  Case Study 2 ndash Diagnosis

                                                                                                                                                                                                                  60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                                                                                                                  Case Study 3 ndash Presentation

                                                                                                                                                                                                                  TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                                                                                                  PT 228 sec 113 ndash 146 sec

                                                                                                                                                                                                                  APTT 45 sec 25 ndash 34 sec

                                                                                                                                                                                                                  D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                                                                                                  Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                                                                                                  FV Normal 70-120

                                                                                                                                                                                                                  FVII Normal 55-170

                                                                                                                                                                                                                  FVIII Normal 60-150

                                                                                                                                                                                                                  Protein C Normal 70-130

                                                                                                                                                                                                                  Hb 134 gdL 14-16 gdL

                                                                                                                                                                                                                  WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                                                  ALT 32 IUL 0ndash34 IUL

                                                                                                                                                                                                                  AST 28 IUL 0ndash34 IUL

                                                                                                                                                                                                                  BUN 09 mgdL 08-13 mgdL

                                                                                                                                                                                                                  Case Study 3 ndash Lab Results

                                                                                                                                                                                                                  Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                                                                                                  Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                                                                                                  Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                                                                                                  Case Study 4 ndash Presentation

                                                                                                                                                                                                                  TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                                                                                                  PT 28 sec 113 ndash 146 sec

                                                                                                                                                                                                                  APTT 71 sec 25 ndash 34 sec

                                                                                                                                                                                                                  D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                                                                                                  Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                                                                                                  FV Normal 70-120

                                                                                                                                                                                                                  FVII Normal 55-170

                                                                                                                                                                                                                  FVIII Normal 60-150

                                                                                                                                                                                                                  Protein C Normal 70-130

                                                                                                                                                                                                                  Hb 158 gdL 14-16 gdL

                                                                                                                                                                                                                  WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                                                  ALT 60 IUL 0ndash34 IUL

                                                                                                                                                                                                                  AST 47 IUL 0ndash34 IUL

                                                                                                                                                                                                                  BUN 38 mgdL 08-13 mgdL

                                                                                                                                                                                                                  Case Study 4 ndash Lab Results

                                                                                                                                                                                                                  Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                                                                                                  Case Study 4 ndash Diagnosis

                                                                                                                                                                                                                  55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                                                                                                  Case Study 5 ndash Presentation

                                                                                                                                                                                                                  Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                                  Case Study 5 ndash Lab Results and Time Course

                                                                                                                                                                                                                  Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                                  TEST RESULT REFERENCE RANGE

                                                                                                                                                                                                                  Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                                                                                                  PT 215 sec 103 ndash 128 sec

                                                                                                                                                                                                                  APTT 44 sec 26 ndash 36 sec

                                                                                                                                                                                                                  D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                                                                                                  Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                                                                                                  FII FV FVIII Low Not reported (NR)

                                                                                                                                                                                                                  FVII FIX FX vWF Normal NR

                                                                                                                                                                                                                  Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                                                                                                  DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                                                                                                  dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                                                                                                  (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                                                                                                  (D) Illustration demonstrating repair

                                                                                                                                                                                                                  Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                                                                                                  Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                                  29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                                                                                  Case Study 6 ndash Presentation

                                                                                                                                                                                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                  Case Study 6 ndash Lab Results

                                                                                                                                                                                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                  TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                                                                                  PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                                                                                  INR 658 1 ndash 125

                                                                                                                                                                                                                  APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                                                                                  D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                                                                                  Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                                                                                  Albumin 28 gdL NR

                                                                                                                                                                                                                  Hb 58 gdL NR

                                                                                                                                                                                                                  LDH 1196 UL NR

                                                                                                                                                                                                                  SGPT 144 IU NR

                                                                                                                                                                                                                  SGOT 88 IU NR

                                                                                                                                                                                                                  Bilirubin 32 mgdL NR

                                                                                                                                                                                                                  DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                                                                                  day postop

                                                                                                                                                                                                                  Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                                                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                  HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                                                                                  Case Study 6 ndash Discussion

                                                                                                                                                                                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                  44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                                                                                  Case Study 7 ndash Presentation

                                                                                                                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                  On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                                                                                  Case Study 7 ndash Presentation

                                                                                                                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                  Case Study 7 ndash Lab Results vs Time

                                                                                                                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                  Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                                                                                  Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                  On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                                                                  Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                  DIC Take Home Messages

                                                                                                                                                                                                                  Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                                                                  Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                                                                  DIC

                                                                                                                                                                                                                  Thank you Questions

                                                                                                                                                                                                                  • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                                                                  • Learning Objectives
                                                                                                                                                                                                                  • Slide Number 3
                                                                                                                                                                                                                  • Slide Number 4
                                                                                                                                                                                                                  • Slide Number 5
                                                                                                                                                                                                                  • Slide Number 6
                                                                                                                                                                                                                  • Slide Number 7
                                                                                                                                                                                                                  • Slide Number 8
                                                                                                                                                                                                                  • Wound Sealing
                                                                                                                                                                                                                  • The Three Steps of Hemostasis
                                                                                                                                                                                                                  • Vessel Wall
                                                                                                                                                                                                                  • Slide Number 12
                                                                                                                                                                                                                  • Slide Number 13
                                                                                                                                                                                                                  • Platelet Structure UnactivatedActivated
                                                                                                                                                                                                                  • Primary Hemostasis
                                                                                                                                                                                                                  • Primary Hemostasis Assays
                                                                                                                                                                                                                  • Slide Number 17
                                                                                                                                                                                                                  • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                                                                  • Slide Number 19
                                                                                                                                                                                                                  • Coagulation factors
                                                                                                                                                                                                                  • Coagulation Assay Mechanisms
                                                                                                                                                                                                                  • Slide Number 22
                                                                                                                                                                                                                  • Fibrin Formation
                                                                                                                                                                                                                  • Slide Number 24
                                                                                                                                                                                                                  • Fibrinolysis Overview
                                                                                                                                                                                                                  • Fibrinolysis Overview
                                                                                                                                                                                                                  • Slide Number 27
                                                                                                                                                                                                                  • Fibrinolysis Releases D-dimers
                                                                                                                                                                                                                  • Basic Pathophysiology of DIC
                                                                                                                                                                                                                  • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                                                                  • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                                                                  • Clinical Conditions Associated With DIC
                                                                                                                                                                                                                  • Frequency of DIC in Selected Disease States
                                                                                                                                                                                                                  • Underlying Diseases in DIC Patients
                                                                                                                                                                                                                  • Slide Number 36
                                                                                                                                                                                                                  • Slide Number 37
                                                                                                                                                                                                                  • Slide Number 38
                                                                                                                                                                                                                  • Slide Number 39
                                                                                                                                                                                                                  • Pathophysiology of DIC
                                                                                                                                                                                                                  • Pathogenesis of DIC in Sepsis
                                                                                                                                                                                                                  • Host Response in Severe Sepsis
                                                                                                                                                                                                                  • Organ Failure in Severe Sepsis
                                                                                                                                                                                                                  • Mechanism of DIC in Organ Failure
                                                                                                                                                                                                                  • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                                                                  • Slide Number 47
                                                                                                                                                                                                                  • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                                                                  • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                                                                  • Mechanism of DIC
                                                                                                                                                                                                                  • Pathophysiology of DIC
                                                                                                                                                                                                                  • Pathophysiology of DIC - Mechanism
                                                                                                                                                                                                                  • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                                                                  • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                                                                  • Pathophysiology of Overt DIC
                                                                                                                                                                                                                  • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                                                                  • Slide Number 57
                                                                                                                                                                                                                  • Slide Number 58
                                                                                                                                                                                                                  • Slide Number 59
                                                                                                                                                                                                                  • Slide Number 60
                                                                                                                                                                                                                  • Slide Number 61
                                                                                                                                                                                                                  • BREAK
                                                                                                                                                                                                                  • Diagnostic and Management Approach for DIC
                                                                                                                                                                                                                  • Diagnosis of DIC
                                                                                                                                                                                                                  • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                                                                  • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                                                                  • Slide Number 67
                                                                                                                                                                                                                  • Slide Number 68
                                                                                                                                                                                                                  • British Journal of Haematology Overt DIC Score
                                                                                                                                                                                                                  • Slide Number 70
                                                                                                                                                                                                                  • Slide Number 71
                                                                                                                                                                                                                  • Slide Number 72
                                                                                                                                                                                                                  • Slide Number 73
                                                                                                                                                                                                                  • DIC Management Goals
                                                                                                                                                                                                                  • DIC Management and Treatment
                                                                                                                                                                                                                  • DIC Management Strategies
                                                                                                                                                                                                                  • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                                                                  • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                                                                  • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                                                                  • D-dimer FDPs and DIC
                                                                                                                                                                                                                  • D-Dimer and FDPs in DIC
                                                                                                                                                                                                                  • Follow Up of DIC State of Disease
                                                                                                                                                                                                                  • FMD-Dimer in DIC Major Differences
                                                                                                                                                                                                                  • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                                                                  • Slide Number 85
                                                                                                                                                                                                                  • Slide Number 86
                                                                                                                                                                                                                  • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                                                                  • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                  • Slide Number 94
                                                                                                                                                                                                                  • Slide Number 95
                                                                                                                                                                                                                  • Slide Number 96
                                                                                                                                                                                                                  • Slide Number 97
                                                                                                                                                                                                                  • Slide Number 98
                                                                                                                                                                                                                  • Slide Number 99
                                                                                                                                                                                                                  • DIC Case Studies
                                                                                                                                                                                                                  • Case Study 1 - Presentation
                                                                                                                                                                                                                  • Case Study 1 ndash Lab Results
                                                                                                                                                                                                                  • Case Study 1 ndash Microscopy
                                                                                                                                                                                                                  • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                                                                  • Slide Number 105
                                                                                                                                                                                                                  • Slide Number 106
                                                                                                                                                                                                                  • Slide Number 107
                                                                                                                                                                                                                  • Slide Number 108
                                                                                                                                                                                                                  • Slide Number 109
                                                                                                                                                                                                                  • Slide Number 110
                                                                                                                                                                                                                  • Slide Number 111
                                                                                                                                                                                                                  • Slide Number 112
                                                                                                                                                                                                                  • Slide Number 113
                                                                                                                                                                                                                  • Slide Number 114
                                                                                                                                                                                                                  • Slide Number 115
                                                                                                                                                                                                                  • Slide Number 116
                                                                                                                                                                                                                  • Slide Number 117
                                                                                                                                                                                                                  • Slide Number 118
                                                                                                                                                                                                                  • Slide Number 119
                                                                                                                                                                                                                  • Slide Number 120
                                                                                                                                                                                                                  • Slide Number 121
                                                                                                                                                                                                                  • Slide Number 122
                                                                                                                                                                                                                  • Slide Number 123
                                                                                                                                                                                                                  • Slide Number 124
                                                                                                                                                                                                                  • Slide Number 125
                                                                                                                                                                                                                  • DIC Take Home Messages
                                                                                                                                                                                                                  • Slide Number 127
                                                                                                                                                                                                                  • Slide Number 128

                                                                                                                                                                                                                    TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L

                                                                                                                                                                                                                    PT 30 sec 113 ndash 146 sec

                                                                                                                                                                                                                    APTT 75 sec 25 ndash 34 sec

                                                                                                                                                                                                                    D-dimer 078 microgml FEU lt050 microgml FEU

                                                                                                                                                                                                                    Fibrinogen 92 mgdl 150-400 mgdl

                                                                                                                                                                                                                    pH 728 738 to 742

                                                                                                                                                                                                                    PaO2 570 mmHg 80-100 mmHg

                                                                                                                                                                                                                    WBC 33 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                                                    ALT 111 IUL 0ndash34 IUL

                                                                                                                                                                                                                    AST 61 IUL 0ndash34 IUL

                                                                                                                                                                                                                    BUN 303 mgdL 08-13 mgdL

                                                                                                                                                                                                                    Case Study 2 ndash Lab Results

                                                                                                                                                                                                                    Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                                                                                                                    Case Study 2 ndash Diagnosis

                                                                                                                                                                                                                    60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                                                                                                                    Case Study 3 ndash Presentation

                                                                                                                                                                                                                    TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                                                                                                    PT 228 sec 113 ndash 146 sec

                                                                                                                                                                                                                    APTT 45 sec 25 ndash 34 sec

                                                                                                                                                                                                                    D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                                                                                                    Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                                                                                                    FV Normal 70-120

                                                                                                                                                                                                                    FVII Normal 55-170

                                                                                                                                                                                                                    FVIII Normal 60-150

                                                                                                                                                                                                                    Protein C Normal 70-130

                                                                                                                                                                                                                    Hb 134 gdL 14-16 gdL

                                                                                                                                                                                                                    WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                                                    ALT 32 IUL 0ndash34 IUL

                                                                                                                                                                                                                    AST 28 IUL 0ndash34 IUL

                                                                                                                                                                                                                    BUN 09 mgdL 08-13 mgdL

                                                                                                                                                                                                                    Case Study 3 ndash Lab Results

                                                                                                                                                                                                                    Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                                                                                                    Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                                                                                                    Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                                                                                                    Case Study 4 ndash Presentation

                                                                                                                                                                                                                    TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                                                                                                    PT 28 sec 113 ndash 146 sec

                                                                                                                                                                                                                    APTT 71 sec 25 ndash 34 sec

                                                                                                                                                                                                                    D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                                                                                                    Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                                                                                                    FV Normal 70-120

                                                                                                                                                                                                                    FVII Normal 55-170

                                                                                                                                                                                                                    FVIII Normal 60-150

                                                                                                                                                                                                                    Protein C Normal 70-130

                                                                                                                                                                                                                    Hb 158 gdL 14-16 gdL

                                                                                                                                                                                                                    WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                                                    ALT 60 IUL 0ndash34 IUL

                                                                                                                                                                                                                    AST 47 IUL 0ndash34 IUL

                                                                                                                                                                                                                    BUN 38 mgdL 08-13 mgdL

                                                                                                                                                                                                                    Case Study 4 ndash Lab Results

                                                                                                                                                                                                                    Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                                                                                                    Case Study 4 ndash Diagnosis

                                                                                                                                                                                                                    55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                                                                                                    Case Study 5 ndash Presentation

                                                                                                                                                                                                                    Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                                    Case Study 5 ndash Lab Results and Time Course

                                                                                                                                                                                                                    Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                                    TEST RESULT REFERENCE RANGE

                                                                                                                                                                                                                    Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                                                                                                    PT 215 sec 103 ndash 128 sec

                                                                                                                                                                                                                    APTT 44 sec 26 ndash 36 sec

                                                                                                                                                                                                                    D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                                                                                                    Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                                                                                                    FII FV FVIII Low Not reported (NR)

                                                                                                                                                                                                                    FVII FIX FX vWF Normal NR

                                                                                                                                                                                                                    Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                                                                                                    DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                                                                                                    dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                                                                                                    (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                                                                                                    (D) Illustration demonstrating repair

                                                                                                                                                                                                                    Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                                                                                                    Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                                    29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                                                                                    Case Study 6 ndash Presentation

                                                                                                                                                                                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                    Case Study 6 ndash Lab Results

                                                                                                                                                                                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                    TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                                                                                    PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                                                                                    INR 658 1 ndash 125

                                                                                                                                                                                                                    APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                                                                                    D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                                                                                    Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                                                                                    Albumin 28 gdL NR

                                                                                                                                                                                                                    Hb 58 gdL NR

                                                                                                                                                                                                                    LDH 1196 UL NR

                                                                                                                                                                                                                    SGPT 144 IU NR

                                                                                                                                                                                                                    SGOT 88 IU NR

                                                                                                                                                                                                                    Bilirubin 32 mgdL NR

                                                                                                                                                                                                                    DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                                                                                    day postop

                                                                                                                                                                                                                    Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                                                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                    HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                                                                                    Case Study 6 ndash Discussion

                                                                                                                                                                                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                    44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                                                                                    Case Study 7 ndash Presentation

                                                                                                                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                    On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                                                                                    Case Study 7 ndash Presentation

                                                                                                                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                    Case Study 7 ndash Lab Results vs Time

                                                                                                                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                    Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                                                                                    Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                    On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                                                                    Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                    DIC Take Home Messages

                                                                                                                                                                                                                    Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                                                                    Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                                                                    DIC

                                                                                                                                                                                                                    Thank you Questions

                                                                                                                                                                                                                    • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                                                                    • Learning Objectives
                                                                                                                                                                                                                    • Slide Number 3
                                                                                                                                                                                                                    • Slide Number 4
                                                                                                                                                                                                                    • Slide Number 5
                                                                                                                                                                                                                    • Slide Number 6
                                                                                                                                                                                                                    • Slide Number 7
                                                                                                                                                                                                                    • Slide Number 8
                                                                                                                                                                                                                    • Wound Sealing
                                                                                                                                                                                                                    • The Three Steps of Hemostasis
                                                                                                                                                                                                                    • Vessel Wall
                                                                                                                                                                                                                    • Slide Number 12
                                                                                                                                                                                                                    • Slide Number 13
                                                                                                                                                                                                                    • Platelet Structure UnactivatedActivated
                                                                                                                                                                                                                    • Primary Hemostasis
                                                                                                                                                                                                                    • Primary Hemostasis Assays
                                                                                                                                                                                                                    • Slide Number 17
                                                                                                                                                                                                                    • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                                                                    • Slide Number 19
                                                                                                                                                                                                                    • Coagulation factors
                                                                                                                                                                                                                    • Coagulation Assay Mechanisms
                                                                                                                                                                                                                    • Slide Number 22
                                                                                                                                                                                                                    • Fibrin Formation
                                                                                                                                                                                                                    • Slide Number 24
                                                                                                                                                                                                                    • Fibrinolysis Overview
                                                                                                                                                                                                                    • Fibrinolysis Overview
                                                                                                                                                                                                                    • Slide Number 27
                                                                                                                                                                                                                    • Fibrinolysis Releases D-dimers
                                                                                                                                                                                                                    • Basic Pathophysiology of DIC
                                                                                                                                                                                                                    • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                                                                    • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                                                                    • Clinical Conditions Associated With DIC
                                                                                                                                                                                                                    • Frequency of DIC in Selected Disease States
                                                                                                                                                                                                                    • Underlying Diseases in DIC Patients
                                                                                                                                                                                                                    • Slide Number 36
                                                                                                                                                                                                                    • Slide Number 37
                                                                                                                                                                                                                    • Slide Number 38
                                                                                                                                                                                                                    • Slide Number 39
                                                                                                                                                                                                                    • Pathophysiology of DIC
                                                                                                                                                                                                                    • Pathogenesis of DIC in Sepsis
                                                                                                                                                                                                                    • Host Response in Severe Sepsis
                                                                                                                                                                                                                    • Organ Failure in Severe Sepsis
                                                                                                                                                                                                                    • Mechanism of DIC in Organ Failure
                                                                                                                                                                                                                    • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                                                                    • Slide Number 47
                                                                                                                                                                                                                    • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                                                                    • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                                                                    • Mechanism of DIC
                                                                                                                                                                                                                    • Pathophysiology of DIC
                                                                                                                                                                                                                    • Pathophysiology of DIC - Mechanism
                                                                                                                                                                                                                    • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                                                                    • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                                                                    • Pathophysiology of Overt DIC
                                                                                                                                                                                                                    • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                                                                    • Slide Number 57
                                                                                                                                                                                                                    • Slide Number 58
                                                                                                                                                                                                                    • Slide Number 59
                                                                                                                                                                                                                    • Slide Number 60
                                                                                                                                                                                                                    • Slide Number 61
                                                                                                                                                                                                                    • BREAK
                                                                                                                                                                                                                    • Diagnostic and Management Approach for DIC
                                                                                                                                                                                                                    • Diagnosis of DIC
                                                                                                                                                                                                                    • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                                                                    • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                                                                    • Slide Number 67
                                                                                                                                                                                                                    • Slide Number 68
                                                                                                                                                                                                                    • British Journal of Haematology Overt DIC Score
                                                                                                                                                                                                                    • Slide Number 70
                                                                                                                                                                                                                    • Slide Number 71
                                                                                                                                                                                                                    • Slide Number 72
                                                                                                                                                                                                                    • Slide Number 73
                                                                                                                                                                                                                    • DIC Management Goals
                                                                                                                                                                                                                    • DIC Management and Treatment
                                                                                                                                                                                                                    • DIC Management Strategies
                                                                                                                                                                                                                    • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                                                                    • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                                                                    • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                                                                    • D-dimer FDPs and DIC
                                                                                                                                                                                                                    • D-Dimer and FDPs in DIC
                                                                                                                                                                                                                    • Follow Up of DIC State of Disease
                                                                                                                                                                                                                    • FMD-Dimer in DIC Major Differences
                                                                                                                                                                                                                    • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                                                                    • Slide Number 85
                                                                                                                                                                                                                    • Slide Number 86
                                                                                                                                                                                                                    • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                                                                    • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                    • Slide Number 94
                                                                                                                                                                                                                    • Slide Number 95
                                                                                                                                                                                                                    • Slide Number 96
                                                                                                                                                                                                                    • Slide Number 97
                                                                                                                                                                                                                    • Slide Number 98
                                                                                                                                                                                                                    • Slide Number 99
                                                                                                                                                                                                                    • DIC Case Studies
                                                                                                                                                                                                                    • Case Study 1 - Presentation
                                                                                                                                                                                                                    • Case Study 1 ndash Lab Results
                                                                                                                                                                                                                    • Case Study 1 ndash Microscopy
                                                                                                                                                                                                                    • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                                                                    • Slide Number 105
                                                                                                                                                                                                                    • Slide Number 106
                                                                                                                                                                                                                    • Slide Number 107
                                                                                                                                                                                                                    • Slide Number 108
                                                                                                                                                                                                                    • Slide Number 109
                                                                                                                                                                                                                    • Slide Number 110
                                                                                                                                                                                                                    • Slide Number 111
                                                                                                                                                                                                                    • Slide Number 112
                                                                                                                                                                                                                    • Slide Number 113
                                                                                                                                                                                                                    • Slide Number 114
                                                                                                                                                                                                                    • Slide Number 115
                                                                                                                                                                                                                    • Slide Number 116
                                                                                                                                                                                                                    • Slide Number 117
                                                                                                                                                                                                                    • Slide Number 118
                                                                                                                                                                                                                    • Slide Number 119
                                                                                                                                                                                                                    • Slide Number 120
                                                                                                                                                                                                                    • Slide Number 121
                                                                                                                                                                                                                    • Slide Number 122
                                                                                                                                                                                                                    • Slide Number 123
                                                                                                                                                                                                                    • Slide Number 124
                                                                                                                                                                                                                    • Slide Number 125
                                                                                                                                                                                                                    • DIC Take Home Messages
                                                                                                                                                                                                                    • Slide Number 127
                                                                                                                                                                                                                    • Slide Number 128

                                                                                                                                                                                                                      Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures

                                                                                                                                                                                                                      Case Study 2 ndash Diagnosis

                                                                                                                                                                                                                      60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                                                                                                                      Case Study 3 ndash Presentation

                                                                                                                                                                                                                      TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                                                                                                      PT 228 sec 113 ndash 146 sec

                                                                                                                                                                                                                      APTT 45 sec 25 ndash 34 sec

                                                                                                                                                                                                                      D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                                                                                                      Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                                                                                                      FV Normal 70-120

                                                                                                                                                                                                                      FVII Normal 55-170

                                                                                                                                                                                                                      FVIII Normal 60-150

                                                                                                                                                                                                                      Protein C Normal 70-130

                                                                                                                                                                                                                      Hb 134 gdL 14-16 gdL

                                                                                                                                                                                                                      WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                                                      ALT 32 IUL 0ndash34 IUL

                                                                                                                                                                                                                      AST 28 IUL 0ndash34 IUL

                                                                                                                                                                                                                      BUN 09 mgdL 08-13 mgdL

                                                                                                                                                                                                                      Case Study 3 ndash Lab Results

                                                                                                                                                                                                                      Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                                                                                                      Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                                                                                                      Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                                                                                                      Case Study 4 ndash Presentation

                                                                                                                                                                                                                      TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                                                                                                      PT 28 sec 113 ndash 146 sec

                                                                                                                                                                                                                      APTT 71 sec 25 ndash 34 sec

                                                                                                                                                                                                                      D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                                                                                                      Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                                                                                                      FV Normal 70-120

                                                                                                                                                                                                                      FVII Normal 55-170

                                                                                                                                                                                                                      FVIII Normal 60-150

                                                                                                                                                                                                                      Protein C Normal 70-130

                                                                                                                                                                                                                      Hb 158 gdL 14-16 gdL

                                                                                                                                                                                                                      WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                                                      ALT 60 IUL 0ndash34 IUL

                                                                                                                                                                                                                      AST 47 IUL 0ndash34 IUL

                                                                                                                                                                                                                      BUN 38 mgdL 08-13 mgdL

                                                                                                                                                                                                                      Case Study 4 ndash Lab Results

                                                                                                                                                                                                                      Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                                                                                                      Case Study 4 ndash Diagnosis

                                                                                                                                                                                                                      55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                                                                                                      Case Study 5 ndash Presentation

                                                                                                                                                                                                                      Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                                      Case Study 5 ndash Lab Results and Time Course

                                                                                                                                                                                                                      Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                                      TEST RESULT REFERENCE RANGE

                                                                                                                                                                                                                      Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                                                                                                      PT 215 sec 103 ndash 128 sec

                                                                                                                                                                                                                      APTT 44 sec 26 ndash 36 sec

                                                                                                                                                                                                                      D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                                                                                                      Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                                                                                                      FII FV FVIII Low Not reported (NR)

                                                                                                                                                                                                                      FVII FIX FX vWF Normal NR

                                                                                                                                                                                                                      Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                                                                                                      DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                                                                                                      dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                                                                                                      (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                                                                                                      (D) Illustration demonstrating repair

                                                                                                                                                                                                                      Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                                                                                                      Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                                      29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                                                                                      Case Study 6 ndash Presentation

                                                                                                                                                                                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                      Case Study 6 ndash Lab Results

                                                                                                                                                                                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                      TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                                                                                      PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                                                                                      INR 658 1 ndash 125

                                                                                                                                                                                                                      APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                                                                                      D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                                                                                      Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                                                                                      Albumin 28 gdL NR

                                                                                                                                                                                                                      Hb 58 gdL NR

                                                                                                                                                                                                                      LDH 1196 UL NR

                                                                                                                                                                                                                      SGPT 144 IU NR

                                                                                                                                                                                                                      SGOT 88 IU NR

                                                                                                                                                                                                                      Bilirubin 32 mgdL NR

                                                                                                                                                                                                                      DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                                                                                      day postop

                                                                                                                                                                                                                      Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                                                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                      HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                                                                                      Case Study 6 ndash Discussion

                                                                                                                                                                                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                      44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                                                                                      Case Study 7 ndash Presentation

                                                                                                                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                      On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                                                                                      Case Study 7 ndash Presentation

                                                                                                                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                      Case Study 7 ndash Lab Results vs Time

                                                                                                                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                      Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                                                                                      Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                      On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                                                                      Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                      DIC Take Home Messages

                                                                                                                                                                                                                      Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                                                                      Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                                                                      DIC

                                                                                                                                                                                                                      Thank you Questions

                                                                                                                                                                                                                      • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                                                                      • Learning Objectives
                                                                                                                                                                                                                      • Slide Number 3
                                                                                                                                                                                                                      • Slide Number 4
                                                                                                                                                                                                                      • Slide Number 5
                                                                                                                                                                                                                      • Slide Number 6
                                                                                                                                                                                                                      • Slide Number 7
                                                                                                                                                                                                                      • Slide Number 8
                                                                                                                                                                                                                      • Wound Sealing
                                                                                                                                                                                                                      • The Three Steps of Hemostasis
                                                                                                                                                                                                                      • Vessel Wall
                                                                                                                                                                                                                      • Slide Number 12
                                                                                                                                                                                                                      • Slide Number 13
                                                                                                                                                                                                                      • Platelet Structure UnactivatedActivated
                                                                                                                                                                                                                      • Primary Hemostasis
                                                                                                                                                                                                                      • Primary Hemostasis Assays
                                                                                                                                                                                                                      • Slide Number 17
                                                                                                                                                                                                                      • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                                                                      • Slide Number 19
                                                                                                                                                                                                                      • Coagulation factors
                                                                                                                                                                                                                      • Coagulation Assay Mechanisms
                                                                                                                                                                                                                      • Slide Number 22
                                                                                                                                                                                                                      • Fibrin Formation
                                                                                                                                                                                                                      • Slide Number 24
                                                                                                                                                                                                                      • Fibrinolysis Overview
                                                                                                                                                                                                                      • Fibrinolysis Overview
                                                                                                                                                                                                                      • Slide Number 27
                                                                                                                                                                                                                      • Fibrinolysis Releases D-dimers
                                                                                                                                                                                                                      • Basic Pathophysiology of DIC
                                                                                                                                                                                                                      • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                                                                      • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                                                                      • Clinical Conditions Associated With DIC
                                                                                                                                                                                                                      • Frequency of DIC in Selected Disease States
                                                                                                                                                                                                                      • Underlying Diseases in DIC Patients
                                                                                                                                                                                                                      • Slide Number 36
                                                                                                                                                                                                                      • Slide Number 37
                                                                                                                                                                                                                      • Slide Number 38
                                                                                                                                                                                                                      • Slide Number 39
                                                                                                                                                                                                                      • Pathophysiology of DIC
                                                                                                                                                                                                                      • Pathogenesis of DIC in Sepsis
                                                                                                                                                                                                                      • Host Response in Severe Sepsis
                                                                                                                                                                                                                      • Organ Failure in Severe Sepsis
                                                                                                                                                                                                                      • Mechanism of DIC in Organ Failure
                                                                                                                                                                                                                      • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                                                                      • Slide Number 47
                                                                                                                                                                                                                      • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                                                                      • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                                                                      • Mechanism of DIC
                                                                                                                                                                                                                      • Pathophysiology of DIC
                                                                                                                                                                                                                      • Pathophysiology of DIC - Mechanism
                                                                                                                                                                                                                      • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                                                                      • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                                                                      • Pathophysiology of Overt DIC
                                                                                                                                                                                                                      • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                                                                      • Slide Number 57
                                                                                                                                                                                                                      • Slide Number 58
                                                                                                                                                                                                                      • Slide Number 59
                                                                                                                                                                                                                      • Slide Number 60
                                                                                                                                                                                                                      • Slide Number 61
                                                                                                                                                                                                                      • BREAK
                                                                                                                                                                                                                      • Diagnostic and Management Approach for DIC
                                                                                                                                                                                                                      • Diagnosis of DIC
                                                                                                                                                                                                                      • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                                                                      • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                                                                      • Slide Number 67
                                                                                                                                                                                                                      • Slide Number 68
                                                                                                                                                                                                                      • British Journal of Haematology Overt DIC Score
                                                                                                                                                                                                                      • Slide Number 70
                                                                                                                                                                                                                      • Slide Number 71
                                                                                                                                                                                                                      • Slide Number 72
                                                                                                                                                                                                                      • Slide Number 73
                                                                                                                                                                                                                      • DIC Management Goals
                                                                                                                                                                                                                      • DIC Management and Treatment
                                                                                                                                                                                                                      • DIC Management Strategies
                                                                                                                                                                                                                      • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                                                                      • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                                                                      • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                                                                      • D-dimer FDPs and DIC
                                                                                                                                                                                                                      • D-Dimer and FDPs in DIC
                                                                                                                                                                                                                      • Follow Up of DIC State of Disease
                                                                                                                                                                                                                      • FMD-Dimer in DIC Major Differences
                                                                                                                                                                                                                      • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                                                                      • Slide Number 85
                                                                                                                                                                                                                      • Slide Number 86
                                                                                                                                                                                                                      • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                                                                      • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                      • Slide Number 94
                                                                                                                                                                                                                      • Slide Number 95
                                                                                                                                                                                                                      • Slide Number 96
                                                                                                                                                                                                                      • Slide Number 97
                                                                                                                                                                                                                      • Slide Number 98
                                                                                                                                                                                                                      • Slide Number 99
                                                                                                                                                                                                                      • DIC Case Studies
                                                                                                                                                                                                                      • Case Study 1 - Presentation
                                                                                                                                                                                                                      • Case Study 1 ndash Lab Results
                                                                                                                                                                                                                      • Case Study 1 ndash Microscopy
                                                                                                                                                                                                                      • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                                                                      • Slide Number 105
                                                                                                                                                                                                                      • Slide Number 106
                                                                                                                                                                                                                      • Slide Number 107
                                                                                                                                                                                                                      • Slide Number 108
                                                                                                                                                                                                                      • Slide Number 109
                                                                                                                                                                                                                      • Slide Number 110
                                                                                                                                                                                                                      • Slide Number 111
                                                                                                                                                                                                                      • Slide Number 112
                                                                                                                                                                                                                      • Slide Number 113
                                                                                                                                                                                                                      • Slide Number 114
                                                                                                                                                                                                                      • Slide Number 115
                                                                                                                                                                                                                      • Slide Number 116
                                                                                                                                                                                                                      • Slide Number 117
                                                                                                                                                                                                                      • Slide Number 118
                                                                                                                                                                                                                      • Slide Number 119
                                                                                                                                                                                                                      • Slide Number 120
                                                                                                                                                                                                                      • Slide Number 121
                                                                                                                                                                                                                      • Slide Number 122
                                                                                                                                                                                                                      • Slide Number 123
                                                                                                                                                                                                                      • Slide Number 124
                                                                                                                                                                                                                      • Slide Number 125
                                                                                                                                                                                                                      • DIC Take Home Messages
                                                                                                                                                                                                                      • Slide Number 127
                                                                                                                                                                                                                      • Slide Number 128

                                                                                                                                                                                                                        60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior

                                                                                                                                                                                                                        Case Study 3 ndash Presentation

                                                                                                                                                                                                                        TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                                                                                                        PT 228 sec 113 ndash 146 sec

                                                                                                                                                                                                                        APTT 45 sec 25 ndash 34 sec

                                                                                                                                                                                                                        D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                                                                                                        Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                                                                                                        FV Normal 70-120

                                                                                                                                                                                                                        FVII Normal 55-170

                                                                                                                                                                                                                        FVIII Normal 60-150

                                                                                                                                                                                                                        Protein C Normal 70-130

                                                                                                                                                                                                                        Hb 134 gdL 14-16 gdL

                                                                                                                                                                                                                        WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                                                        ALT 32 IUL 0ndash34 IUL

                                                                                                                                                                                                                        AST 28 IUL 0ndash34 IUL

                                                                                                                                                                                                                        BUN 09 mgdL 08-13 mgdL

                                                                                                                                                                                                                        Case Study 3 ndash Lab Results

                                                                                                                                                                                                                        Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                                                                                                        Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                                                                                                        Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                                                                                                        Case Study 4 ndash Presentation

                                                                                                                                                                                                                        TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                                                                                                        PT 28 sec 113 ndash 146 sec

                                                                                                                                                                                                                        APTT 71 sec 25 ndash 34 sec

                                                                                                                                                                                                                        D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                                                                                                        Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                                                                                                        FV Normal 70-120

                                                                                                                                                                                                                        FVII Normal 55-170

                                                                                                                                                                                                                        FVIII Normal 60-150

                                                                                                                                                                                                                        Protein C Normal 70-130

                                                                                                                                                                                                                        Hb 158 gdL 14-16 gdL

                                                                                                                                                                                                                        WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                                                        ALT 60 IUL 0ndash34 IUL

                                                                                                                                                                                                                        AST 47 IUL 0ndash34 IUL

                                                                                                                                                                                                                        BUN 38 mgdL 08-13 mgdL

                                                                                                                                                                                                                        Case Study 4 ndash Lab Results

                                                                                                                                                                                                                        Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                                                                                                        Case Study 4 ndash Diagnosis

                                                                                                                                                                                                                        55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                                                                                                        Case Study 5 ndash Presentation

                                                                                                                                                                                                                        Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                                        Case Study 5 ndash Lab Results and Time Course

                                                                                                                                                                                                                        Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                                        TEST RESULT REFERENCE RANGE

                                                                                                                                                                                                                        Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                                                                                                        PT 215 sec 103 ndash 128 sec

                                                                                                                                                                                                                        APTT 44 sec 26 ndash 36 sec

                                                                                                                                                                                                                        D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                                                                                                        Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                                                                                                        FII FV FVIII Low Not reported (NR)

                                                                                                                                                                                                                        FVII FIX FX vWF Normal NR

                                                                                                                                                                                                                        Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                                                                                                        DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                                                                                                        dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                                                                                                        (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                                                                                                        (D) Illustration demonstrating repair

                                                                                                                                                                                                                        Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                                                                                                        Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                                        29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                                                                                        Case Study 6 ndash Presentation

                                                                                                                                                                                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                        Case Study 6 ndash Lab Results

                                                                                                                                                                                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                        TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                                                                                        PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                                                                                        INR 658 1 ndash 125

                                                                                                                                                                                                                        APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                                                                                        D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                                                                                        Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                                                                                        Albumin 28 gdL NR

                                                                                                                                                                                                                        Hb 58 gdL NR

                                                                                                                                                                                                                        LDH 1196 UL NR

                                                                                                                                                                                                                        SGPT 144 IU NR

                                                                                                                                                                                                                        SGOT 88 IU NR

                                                                                                                                                                                                                        Bilirubin 32 mgdL NR

                                                                                                                                                                                                                        DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                                                                                        day postop

                                                                                                                                                                                                                        Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                                                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                        HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                                                                                        Case Study 6 ndash Discussion

                                                                                                                                                                                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                        44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                                                                                        Case Study 7 ndash Presentation

                                                                                                                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                        On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                                                                                        Case Study 7 ndash Presentation

                                                                                                                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                        Case Study 7 ndash Lab Results vs Time

                                                                                                                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                        Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                                                                                        Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                        On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                                                                        Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                        DIC Take Home Messages

                                                                                                                                                                                                                        Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                                                                        Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                                                                        DIC

                                                                                                                                                                                                                        Thank you Questions

                                                                                                                                                                                                                        • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                                                                        • Learning Objectives
                                                                                                                                                                                                                        • Slide Number 3
                                                                                                                                                                                                                        • Slide Number 4
                                                                                                                                                                                                                        • Slide Number 5
                                                                                                                                                                                                                        • Slide Number 6
                                                                                                                                                                                                                        • Slide Number 7
                                                                                                                                                                                                                        • Slide Number 8
                                                                                                                                                                                                                        • Wound Sealing
                                                                                                                                                                                                                        • The Three Steps of Hemostasis
                                                                                                                                                                                                                        • Vessel Wall
                                                                                                                                                                                                                        • Slide Number 12
                                                                                                                                                                                                                        • Slide Number 13
                                                                                                                                                                                                                        • Platelet Structure UnactivatedActivated
                                                                                                                                                                                                                        • Primary Hemostasis
                                                                                                                                                                                                                        • Primary Hemostasis Assays
                                                                                                                                                                                                                        • Slide Number 17
                                                                                                                                                                                                                        • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                                                                        • Slide Number 19
                                                                                                                                                                                                                        • Coagulation factors
                                                                                                                                                                                                                        • Coagulation Assay Mechanisms
                                                                                                                                                                                                                        • Slide Number 22
                                                                                                                                                                                                                        • Fibrin Formation
                                                                                                                                                                                                                        • Slide Number 24
                                                                                                                                                                                                                        • Fibrinolysis Overview
                                                                                                                                                                                                                        • Fibrinolysis Overview
                                                                                                                                                                                                                        • Slide Number 27
                                                                                                                                                                                                                        • Fibrinolysis Releases D-dimers
                                                                                                                                                                                                                        • Basic Pathophysiology of DIC
                                                                                                                                                                                                                        • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                                                                        • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                                                                        • Clinical Conditions Associated With DIC
                                                                                                                                                                                                                        • Frequency of DIC in Selected Disease States
                                                                                                                                                                                                                        • Underlying Diseases in DIC Patients
                                                                                                                                                                                                                        • Slide Number 36
                                                                                                                                                                                                                        • Slide Number 37
                                                                                                                                                                                                                        • Slide Number 38
                                                                                                                                                                                                                        • Slide Number 39
                                                                                                                                                                                                                        • Pathophysiology of DIC
                                                                                                                                                                                                                        • Pathogenesis of DIC in Sepsis
                                                                                                                                                                                                                        • Host Response in Severe Sepsis
                                                                                                                                                                                                                        • Organ Failure in Severe Sepsis
                                                                                                                                                                                                                        • Mechanism of DIC in Organ Failure
                                                                                                                                                                                                                        • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                                                                        • Slide Number 47
                                                                                                                                                                                                                        • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                                                                        • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                                                                        • Mechanism of DIC
                                                                                                                                                                                                                        • Pathophysiology of DIC
                                                                                                                                                                                                                        • Pathophysiology of DIC - Mechanism
                                                                                                                                                                                                                        • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                                                                        • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                                                                        • Pathophysiology of Overt DIC
                                                                                                                                                                                                                        • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                                                                        • Slide Number 57
                                                                                                                                                                                                                        • Slide Number 58
                                                                                                                                                                                                                        • Slide Number 59
                                                                                                                                                                                                                        • Slide Number 60
                                                                                                                                                                                                                        • Slide Number 61
                                                                                                                                                                                                                        • BREAK
                                                                                                                                                                                                                        • Diagnostic and Management Approach for DIC
                                                                                                                                                                                                                        • Diagnosis of DIC
                                                                                                                                                                                                                        • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                                                                        • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                                                                        • Slide Number 67
                                                                                                                                                                                                                        • Slide Number 68
                                                                                                                                                                                                                        • British Journal of Haematology Overt DIC Score
                                                                                                                                                                                                                        • Slide Number 70
                                                                                                                                                                                                                        • Slide Number 71
                                                                                                                                                                                                                        • Slide Number 72
                                                                                                                                                                                                                        • Slide Number 73
                                                                                                                                                                                                                        • DIC Management Goals
                                                                                                                                                                                                                        • DIC Management and Treatment
                                                                                                                                                                                                                        • DIC Management Strategies
                                                                                                                                                                                                                        • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                                                                        • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                                                                        • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                                                                        • D-dimer FDPs and DIC
                                                                                                                                                                                                                        • D-Dimer and FDPs in DIC
                                                                                                                                                                                                                        • Follow Up of DIC State of Disease
                                                                                                                                                                                                                        • FMD-Dimer in DIC Major Differences
                                                                                                                                                                                                                        • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                                                                        • Slide Number 85
                                                                                                                                                                                                                        • Slide Number 86
                                                                                                                                                                                                                        • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                                                                        • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                        • Slide Number 94
                                                                                                                                                                                                                        • Slide Number 95
                                                                                                                                                                                                                        • Slide Number 96
                                                                                                                                                                                                                        • Slide Number 97
                                                                                                                                                                                                                        • Slide Number 98
                                                                                                                                                                                                                        • Slide Number 99
                                                                                                                                                                                                                        • DIC Case Studies
                                                                                                                                                                                                                        • Case Study 1 - Presentation
                                                                                                                                                                                                                        • Case Study 1 ndash Lab Results
                                                                                                                                                                                                                        • Case Study 1 ndash Microscopy
                                                                                                                                                                                                                        • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                                                                        • Slide Number 105
                                                                                                                                                                                                                        • Slide Number 106
                                                                                                                                                                                                                        • Slide Number 107
                                                                                                                                                                                                                        • Slide Number 108
                                                                                                                                                                                                                        • Slide Number 109
                                                                                                                                                                                                                        • Slide Number 110
                                                                                                                                                                                                                        • Slide Number 111
                                                                                                                                                                                                                        • Slide Number 112
                                                                                                                                                                                                                        • Slide Number 113
                                                                                                                                                                                                                        • Slide Number 114
                                                                                                                                                                                                                        • Slide Number 115
                                                                                                                                                                                                                        • Slide Number 116
                                                                                                                                                                                                                        • Slide Number 117
                                                                                                                                                                                                                        • Slide Number 118
                                                                                                                                                                                                                        • Slide Number 119
                                                                                                                                                                                                                        • Slide Number 120
                                                                                                                                                                                                                        • Slide Number 121
                                                                                                                                                                                                                        • Slide Number 122
                                                                                                                                                                                                                        • Slide Number 123
                                                                                                                                                                                                                        • Slide Number 124
                                                                                                                                                                                                                        • Slide Number 125
                                                                                                                                                                                                                        • DIC Take Home Messages
                                                                                                                                                                                                                        • Slide Number 127
                                                                                                                                                                                                                        • Slide Number 128

                                                                                                                                                                                                                          TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L

                                                                                                                                                                                                                          PT 228 sec 113 ndash 146 sec

                                                                                                                                                                                                                          APTT 45 sec 25 ndash 34 sec

                                                                                                                                                                                                                          D-dimer 080 microgml FEU lt050 microgmL FEU

                                                                                                                                                                                                                          Fibrinogen 82 mgdL 150-400 mgdL

                                                                                                                                                                                                                          FV Normal 70-120

                                                                                                                                                                                                                          FVII Normal 55-170

                                                                                                                                                                                                                          FVIII Normal 60-150

                                                                                                                                                                                                                          Protein C Normal 70-130

                                                                                                                                                                                                                          Hb 134 gdL 14-16 gdL

                                                                                                                                                                                                                          WBC 81 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                                                          ALT 32 IUL 0ndash34 IUL

                                                                                                                                                                                                                          AST 28 IUL 0ndash34 IUL

                                                                                                                                                                                                                          BUN 09 mgdL 08-13 mgdL

                                                                                                                                                                                                                          Case Study 3 ndash Lab Results

                                                                                                                                                                                                                          Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                                                                                                          Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                                                                                                          Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                                                                                                          Case Study 4 ndash Presentation

                                                                                                                                                                                                                          TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                                                                                                          PT 28 sec 113 ndash 146 sec

                                                                                                                                                                                                                          APTT 71 sec 25 ndash 34 sec

                                                                                                                                                                                                                          D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                                                                                                          Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                                                                                                          FV Normal 70-120

                                                                                                                                                                                                                          FVII Normal 55-170

                                                                                                                                                                                                                          FVIII Normal 60-150

                                                                                                                                                                                                                          Protein C Normal 70-130

                                                                                                                                                                                                                          Hb 158 gdL 14-16 gdL

                                                                                                                                                                                                                          WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                                                          ALT 60 IUL 0ndash34 IUL

                                                                                                                                                                                                                          AST 47 IUL 0ndash34 IUL

                                                                                                                                                                                                                          BUN 38 mgdL 08-13 mgdL

                                                                                                                                                                                                                          Case Study 4 ndash Lab Results

                                                                                                                                                                                                                          Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                                                                                                          Case Study 4 ndash Diagnosis

                                                                                                                                                                                                                          55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                                                                                                          Case Study 5 ndash Presentation

                                                                                                                                                                                                                          Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                                          Case Study 5 ndash Lab Results and Time Course

                                                                                                                                                                                                                          Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                                          TEST RESULT REFERENCE RANGE

                                                                                                                                                                                                                          Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                                                                                                          PT 215 sec 103 ndash 128 sec

                                                                                                                                                                                                                          APTT 44 sec 26 ndash 36 sec

                                                                                                                                                                                                                          D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                                                                                                          Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                                                                                                          FII FV FVIII Low Not reported (NR)

                                                                                                                                                                                                                          FVII FIX FX vWF Normal NR

                                                                                                                                                                                                                          Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                                                                                                          DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                                                                                                          dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                                                                                                          (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                                                                                                          (D) Illustration demonstrating repair

                                                                                                                                                                                                                          Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                                                                                                          Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                                          29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                                                                                          Case Study 6 ndash Presentation

                                                                                                                                                                                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                          Case Study 6 ndash Lab Results

                                                                                                                                                                                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                          TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                                                                                          PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                                                                                          INR 658 1 ndash 125

                                                                                                                                                                                                                          APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                                                                                          D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                                                                                          Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                                                                                          Albumin 28 gdL NR

                                                                                                                                                                                                                          Hb 58 gdL NR

                                                                                                                                                                                                                          LDH 1196 UL NR

                                                                                                                                                                                                                          SGPT 144 IU NR

                                                                                                                                                                                                                          SGOT 88 IU NR

                                                                                                                                                                                                                          Bilirubin 32 mgdL NR

                                                                                                                                                                                                                          DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                                                                                          day postop

                                                                                                                                                                                                                          Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                                                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                          HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                                                                                          Case Study 6 ndash Discussion

                                                                                                                                                                                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                          44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                                                                                          Case Study 7 ndash Presentation

                                                                                                                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                          On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                                                                                          Case Study 7 ndash Presentation

                                                                                                                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                          Case Study 7 ndash Lab Results vs Time

                                                                                                                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                          Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                                                                                          Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                          On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                                                                          Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                          DIC Take Home Messages

                                                                                                                                                                                                                          Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                                                                          Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                                                                          DIC

                                                                                                                                                                                                                          Thank you Questions

                                                                                                                                                                                                                          • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                                                                          • Learning Objectives
                                                                                                                                                                                                                          • Slide Number 3
                                                                                                                                                                                                                          • Slide Number 4
                                                                                                                                                                                                                          • Slide Number 5
                                                                                                                                                                                                                          • Slide Number 6
                                                                                                                                                                                                                          • Slide Number 7
                                                                                                                                                                                                                          • Slide Number 8
                                                                                                                                                                                                                          • Wound Sealing
                                                                                                                                                                                                                          • The Three Steps of Hemostasis
                                                                                                                                                                                                                          • Vessel Wall
                                                                                                                                                                                                                          • Slide Number 12
                                                                                                                                                                                                                          • Slide Number 13
                                                                                                                                                                                                                          • Platelet Structure UnactivatedActivated
                                                                                                                                                                                                                          • Primary Hemostasis
                                                                                                                                                                                                                          • Primary Hemostasis Assays
                                                                                                                                                                                                                          • Slide Number 17
                                                                                                                                                                                                                          • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                                                                          • Slide Number 19
                                                                                                                                                                                                                          • Coagulation factors
                                                                                                                                                                                                                          • Coagulation Assay Mechanisms
                                                                                                                                                                                                                          • Slide Number 22
                                                                                                                                                                                                                          • Fibrin Formation
                                                                                                                                                                                                                          • Slide Number 24
                                                                                                                                                                                                                          • Fibrinolysis Overview
                                                                                                                                                                                                                          • Fibrinolysis Overview
                                                                                                                                                                                                                          • Slide Number 27
                                                                                                                                                                                                                          • Fibrinolysis Releases D-dimers
                                                                                                                                                                                                                          • Basic Pathophysiology of DIC
                                                                                                                                                                                                                          • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                                                                          • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                                                                          • Clinical Conditions Associated With DIC
                                                                                                                                                                                                                          • Frequency of DIC in Selected Disease States
                                                                                                                                                                                                                          • Underlying Diseases in DIC Patients
                                                                                                                                                                                                                          • Slide Number 36
                                                                                                                                                                                                                          • Slide Number 37
                                                                                                                                                                                                                          • Slide Number 38
                                                                                                                                                                                                                          • Slide Number 39
                                                                                                                                                                                                                          • Pathophysiology of DIC
                                                                                                                                                                                                                          • Pathogenesis of DIC in Sepsis
                                                                                                                                                                                                                          • Host Response in Severe Sepsis
                                                                                                                                                                                                                          • Organ Failure in Severe Sepsis
                                                                                                                                                                                                                          • Mechanism of DIC in Organ Failure
                                                                                                                                                                                                                          • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                                                                          • Slide Number 47
                                                                                                                                                                                                                          • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                                                                          • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                                                                          • Mechanism of DIC
                                                                                                                                                                                                                          • Pathophysiology of DIC
                                                                                                                                                                                                                          • Pathophysiology of DIC - Mechanism
                                                                                                                                                                                                                          • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                                                                          • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                                                                          • Pathophysiology of Overt DIC
                                                                                                                                                                                                                          • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                                                                          • Slide Number 57
                                                                                                                                                                                                                          • Slide Number 58
                                                                                                                                                                                                                          • Slide Number 59
                                                                                                                                                                                                                          • Slide Number 60
                                                                                                                                                                                                                          • Slide Number 61
                                                                                                                                                                                                                          • BREAK
                                                                                                                                                                                                                          • Diagnostic and Management Approach for DIC
                                                                                                                                                                                                                          • Diagnosis of DIC
                                                                                                                                                                                                                          • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                                                                          • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                                                                          • Slide Number 67
                                                                                                                                                                                                                          • Slide Number 68
                                                                                                                                                                                                                          • British Journal of Haematology Overt DIC Score
                                                                                                                                                                                                                          • Slide Number 70
                                                                                                                                                                                                                          • Slide Number 71
                                                                                                                                                                                                                          • Slide Number 72
                                                                                                                                                                                                                          • Slide Number 73
                                                                                                                                                                                                                          • DIC Management Goals
                                                                                                                                                                                                                          • DIC Management and Treatment
                                                                                                                                                                                                                          • DIC Management Strategies
                                                                                                                                                                                                                          • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                                                                          • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                                                                          • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                                                                          • D-dimer FDPs and DIC
                                                                                                                                                                                                                          • D-Dimer and FDPs in DIC
                                                                                                                                                                                                                          • Follow Up of DIC State of Disease
                                                                                                                                                                                                                          • FMD-Dimer in DIC Major Differences
                                                                                                                                                                                                                          • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                                                                          • Slide Number 85
                                                                                                                                                                                                                          • Slide Number 86
                                                                                                                                                                                                                          • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                                                                          • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                          • Slide Number 94
                                                                                                                                                                                                                          • Slide Number 95
                                                                                                                                                                                                                          • Slide Number 96
                                                                                                                                                                                                                          • Slide Number 97
                                                                                                                                                                                                                          • Slide Number 98
                                                                                                                                                                                                                          • Slide Number 99
                                                                                                                                                                                                                          • DIC Case Studies
                                                                                                                                                                                                                          • Case Study 1 - Presentation
                                                                                                                                                                                                                          • Case Study 1 ndash Lab Results
                                                                                                                                                                                                                          • Case Study 1 ndash Microscopy
                                                                                                                                                                                                                          • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                                                                          • Slide Number 105
                                                                                                                                                                                                                          • Slide Number 106
                                                                                                                                                                                                                          • Slide Number 107
                                                                                                                                                                                                                          • Slide Number 108
                                                                                                                                                                                                                          • Slide Number 109
                                                                                                                                                                                                                          • Slide Number 110
                                                                                                                                                                                                                          • Slide Number 111
                                                                                                                                                                                                                          • Slide Number 112
                                                                                                                                                                                                                          • Slide Number 113
                                                                                                                                                                                                                          • Slide Number 114
                                                                                                                                                                                                                          • Slide Number 115
                                                                                                                                                                                                                          • Slide Number 116
                                                                                                                                                                                                                          • Slide Number 117
                                                                                                                                                                                                                          • Slide Number 118
                                                                                                                                                                                                                          • Slide Number 119
                                                                                                                                                                                                                          • Slide Number 120
                                                                                                                                                                                                                          • Slide Number 121
                                                                                                                                                                                                                          • Slide Number 122
                                                                                                                                                                                                                          • Slide Number 123
                                                                                                                                                                                                                          • Slide Number 124
                                                                                                                                                                                                                          • Slide Number 125
                                                                                                                                                                                                                          • DIC Take Home Messages
                                                                                                                                                                                                                          • Slide Number 127
                                                                                                                                                                                                                          • Slide Number 128

                                                                                                                                                                                                                            Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment

                                                                                                                                                                                                                            Case Study 3 ndash Diagnosis and Therapy

                                                                                                                                                                                                                            Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                                                                                                            Case Study 4 ndash Presentation

                                                                                                                                                                                                                            TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                                                                                                            PT 28 sec 113 ndash 146 sec

                                                                                                                                                                                                                            APTT 71 sec 25 ndash 34 sec

                                                                                                                                                                                                                            D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                                                                                                            Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                                                                                                            FV Normal 70-120

                                                                                                                                                                                                                            FVII Normal 55-170

                                                                                                                                                                                                                            FVIII Normal 60-150

                                                                                                                                                                                                                            Protein C Normal 70-130

                                                                                                                                                                                                                            Hb 158 gdL 14-16 gdL

                                                                                                                                                                                                                            WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                                                            ALT 60 IUL 0ndash34 IUL

                                                                                                                                                                                                                            AST 47 IUL 0ndash34 IUL

                                                                                                                                                                                                                            BUN 38 mgdL 08-13 mgdL

                                                                                                                                                                                                                            Case Study 4 ndash Lab Results

                                                                                                                                                                                                                            Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                                                                                                            Case Study 4 ndash Diagnosis

                                                                                                                                                                                                                            55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                                                                                                            Case Study 5 ndash Presentation

                                                                                                                                                                                                                            Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                                            Case Study 5 ndash Lab Results and Time Course

                                                                                                                                                                                                                            Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                                            TEST RESULT REFERENCE RANGE

                                                                                                                                                                                                                            Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                                                                                                            PT 215 sec 103 ndash 128 sec

                                                                                                                                                                                                                            APTT 44 sec 26 ndash 36 sec

                                                                                                                                                                                                                            D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                                                                                                            Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                                                                                                            FII FV FVIII Low Not reported (NR)

                                                                                                                                                                                                                            FVII FIX FX vWF Normal NR

                                                                                                                                                                                                                            Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                                                                                                            DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                                                                                                            dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                                                                                                            (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                                                                                                            (D) Illustration demonstrating repair

                                                                                                                                                                                                                            Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                                                                                                            Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                                            29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                                                                                            Case Study 6 ndash Presentation

                                                                                                                                                                                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                            Case Study 6 ndash Lab Results

                                                                                                                                                                                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                            TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                                                                                            PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                                                                                            INR 658 1 ndash 125

                                                                                                                                                                                                                            APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                                                                                            D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                                                                                            Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                                                                                            Albumin 28 gdL NR

                                                                                                                                                                                                                            Hb 58 gdL NR

                                                                                                                                                                                                                            LDH 1196 UL NR

                                                                                                                                                                                                                            SGPT 144 IU NR

                                                                                                                                                                                                                            SGOT 88 IU NR

                                                                                                                                                                                                                            Bilirubin 32 mgdL NR

                                                                                                                                                                                                                            DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                                                                                            day postop

                                                                                                                                                                                                                            Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                                                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                            HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                                                                                            Case Study 6 ndash Discussion

                                                                                                                                                                                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                            44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                                                                                            Case Study 7 ndash Presentation

                                                                                                                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                            On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                                                                                            Case Study 7 ndash Presentation

                                                                                                                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                            Case Study 7 ndash Lab Results vs Time

                                                                                                                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                            Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                                                                                            Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                            On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                                                                            Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                            DIC Take Home Messages

                                                                                                                                                                                                                            Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                                                                            Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                                                                            DIC

                                                                                                                                                                                                                            Thank you Questions

                                                                                                                                                                                                                            • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                                                                            • Learning Objectives
                                                                                                                                                                                                                            • Slide Number 3
                                                                                                                                                                                                                            • Slide Number 4
                                                                                                                                                                                                                            • Slide Number 5
                                                                                                                                                                                                                            • Slide Number 6
                                                                                                                                                                                                                            • Slide Number 7
                                                                                                                                                                                                                            • Slide Number 8
                                                                                                                                                                                                                            • Wound Sealing
                                                                                                                                                                                                                            • The Three Steps of Hemostasis
                                                                                                                                                                                                                            • Vessel Wall
                                                                                                                                                                                                                            • Slide Number 12
                                                                                                                                                                                                                            • Slide Number 13
                                                                                                                                                                                                                            • Platelet Structure UnactivatedActivated
                                                                                                                                                                                                                            • Primary Hemostasis
                                                                                                                                                                                                                            • Primary Hemostasis Assays
                                                                                                                                                                                                                            • Slide Number 17
                                                                                                                                                                                                                            • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                                                                            • Slide Number 19
                                                                                                                                                                                                                            • Coagulation factors
                                                                                                                                                                                                                            • Coagulation Assay Mechanisms
                                                                                                                                                                                                                            • Slide Number 22
                                                                                                                                                                                                                            • Fibrin Formation
                                                                                                                                                                                                                            • Slide Number 24
                                                                                                                                                                                                                            • Fibrinolysis Overview
                                                                                                                                                                                                                            • Fibrinolysis Overview
                                                                                                                                                                                                                            • Slide Number 27
                                                                                                                                                                                                                            • Fibrinolysis Releases D-dimers
                                                                                                                                                                                                                            • Basic Pathophysiology of DIC
                                                                                                                                                                                                                            • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                                                                            • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                                                                            • Clinical Conditions Associated With DIC
                                                                                                                                                                                                                            • Frequency of DIC in Selected Disease States
                                                                                                                                                                                                                            • Underlying Diseases in DIC Patients
                                                                                                                                                                                                                            • Slide Number 36
                                                                                                                                                                                                                            • Slide Number 37
                                                                                                                                                                                                                            • Slide Number 38
                                                                                                                                                                                                                            • Slide Number 39
                                                                                                                                                                                                                            • Pathophysiology of DIC
                                                                                                                                                                                                                            • Pathogenesis of DIC in Sepsis
                                                                                                                                                                                                                            • Host Response in Severe Sepsis
                                                                                                                                                                                                                            • Organ Failure in Severe Sepsis
                                                                                                                                                                                                                            • Mechanism of DIC in Organ Failure
                                                                                                                                                                                                                            • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                                                                            • Slide Number 47
                                                                                                                                                                                                                            • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                                                                            • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                                                                            • Mechanism of DIC
                                                                                                                                                                                                                            • Pathophysiology of DIC
                                                                                                                                                                                                                            • Pathophysiology of DIC - Mechanism
                                                                                                                                                                                                                            • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                                                                            • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                                                                            • Pathophysiology of Overt DIC
                                                                                                                                                                                                                            • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                                                                            • Slide Number 57
                                                                                                                                                                                                                            • Slide Number 58
                                                                                                                                                                                                                            • Slide Number 59
                                                                                                                                                                                                                            • Slide Number 60
                                                                                                                                                                                                                            • Slide Number 61
                                                                                                                                                                                                                            • BREAK
                                                                                                                                                                                                                            • Diagnostic and Management Approach for DIC
                                                                                                                                                                                                                            • Diagnosis of DIC
                                                                                                                                                                                                                            • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                                                                            • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                                                                            • Slide Number 67
                                                                                                                                                                                                                            • Slide Number 68
                                                                                                                                                                                                                            • British Journal of Haematology Overt DIC Score
                                                                                                                                                                                                                            • Slide Number 70
                                                                                                                                                                                                                            • Slide Number 71
                                                                                                                                                                                                                            • Slide Number 72
                                                                                                                                                                                                                            • Slide Number 73
                                                                                                                                                                                                                            • DIC Management Goals
                                                                                                                                                                                                                            • DIC Management and Treatment
                                                                                                                                                                                                                            • DIC Management Strategies
                                                                                                                                                                                                                            • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                                                                            • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                                                                            • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                                                                            • D-dimer FDPs and DIC
                                                                                                                                                                                                                            • D-Dimer and FDPs in DIC
                                                                                                                                                                                                                            • Follow Up of DIC State of Disease
                                                                                                                                                                                                                            • FMD-Dimer in DIC Major Differences
                                                                                                                                                                                                                            • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                                                                            • Slide Number 85
                                                                                                                                                                                                                            • Slide Number 86
                                                                                                                                                                                                                            • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                                                                            • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                            • Slide Number 94
                                                                                                                                                                                                                            • Slide Number 95
                                                                                                                                                                                                                            • Slide Number 96
                                                                                                                                                                                                                            • Slide Number 97
                                                                                                                                                                                                                            • Slide Number 98
                                                                                                                                                                                                                            • Slide Number 99
                                                                                                                                                                                                                            • DIC Case Studies
                                                                                                                                                                                                                            • Case Study 1 - Presentation
                                                                                                                                                                                                                            • Case Study 1 ndash Lab Results
                                                                                                                                                                                                                            • Case Study 1 ndash Microscopy
                                                                                                                                                                                                                            • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                                                                            • Slide Number 105
                                                                                                                                                                                                                            • Slide Number 106
                                                                                                                                                                                                                            • Slide Number 107
                                                                                                                                                                                                                            • Slide Number 108
                                                                                                                                                                                                                            • Slide Number 109
                                                                                                                                                                                                                            • Slide Number 110
                                                                                                                                                                                                                            • Slide Number 111
                                                                                                                                                                                                                            • Slide Number 112
                                                                                                                                                                                                                            • Slide Number 113
                                                                                                                                                                                                                            • Slide Number 114
                                                                                                                                                                                                                            • Slide Number 115
                                                                                                                                                                                                                            • Slide Number 116
                                                                                                                                                                                                                            • Slide Number 117
                                                                                                                                                                                                                            • Slide Number 118
                                                                                                                                                                                                                            • Slide Number 119
                                                                                                                                                                                                                            • Slide Number 120
                                                                                                                                                                                                                            • Slide Number 121
                                                                                                                                                                                                                            • Slide Number 122
                                                                                                                                                                                                                            • Slide Number 123
                                                                                                                                                                                                                            • Slide Number 124
                                                                                                                                                                                                                            • Slide Number 125
                                                                                                                                                                                                                            • DIC Take Home Messages
                                                                                                                                                                                                                            • Slide Number 127
                                                                                                                                                                                                                            • Slide Number 128

                                                                                                                                                                                                                              Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91

                                                                                                                                                                                                                              Case Study 4 ndash Presentation

                                                                                                                                                                                                                              TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                                                                                                              PT 28 sec 113 ndash 146 sec

                                                                                                                                                                                                                              APTT 71 sec 25 ndash 34 sec

                                                                                                                                                                                                                              D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                                                                                                              Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                                                                                                              FV Normal 70-120

                                                                                                                                                                                                                              FVII Normal 55-170

                                                                                                                                                                                                                              FVIII Normal 60-150

                                                                                                                                                                                                                              Protein C Normal 70-130

                                                                                                                                                                                                                              Hb 158 gdL 14-16 gdL

                                                                                                                                                                                                                              WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                                                              ALT 60 IUL 0ndash34 IUL

                                                                                                                                                                                                                              AST 47 IUL 0ndash34 IUL

                                                                                                                                                                                                                              BUN 38 mgdL 08-13 mgdL

                                                                                                                                                                                                                              Case Study 4 ndash Lab Results

                                                                                                                                                                                                                              Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                                                                                                              Case Study 4 ndash Diagnosis

                                                                                                                                                                                                                              55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                                                                                                              Case Study 5 ndash Presentation

                                                                                                                                                                                                                              Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                                              Case Study 5 ndash Lab Results and Time Course

                                                                                                                                                                                                                              Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                                              TEST RESULT REFERENCE RANGE

                                                                                                                                                                                                                              Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                                                                                                              PT 215 sec 103 ndash 128 sec

                                                                                                                                                                                                                              APTT 44 sec 26 ndash 36 sec

                                                                                                                                                                                                                              D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                                                                                                              Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                                                                                                              FII FV FVIII Low Not reported (NR)

                                                                                                                                                                                                                              FVII FIX FX vWF Normal NR

                                                                                                                                                                                                                              Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                                                                                                              DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                                                                                                              dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                                                                                                              (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                                                                                                              (D) Illustration demonstrating repair

                                                                                                                                                                                                                              Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                                                                                                              Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                                              29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                                                                                              Case Study 6 ndash Presentation

                                                                                                                                                                                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                              Case Study 6 ndash Lab Results

                                                                                                                                                                                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                              TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                                                                                              PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                                                                                              INR 658 1 ndash 125

                                                                                                                                                                                                                              APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                                                                                              D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                                                                                              Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                                                                                              Albumin 28 gdL NR

                                                                                                                                                                                                                              Hb 58 gdL NR

                                                                                                                                                                                                                              LDH 1196 UL NR

                                                                                                                                                                                                                              SGPT 144 IU NR

                                                                                                                                                                                                                              SGOT 88 IU NR

                                                                                                                                                                                                                              Bilirubin 32 mgdL NR

                                                                                                                                                                                                                              DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                                                                                              day postop

                                                                                                                                                                                                                              Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                                                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                              HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                                                                                              Case Study 6 ndash Discussion

                                                                                                                                                                                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                              44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                                                                                              Case Study 7 ndash Presentation

                                                                                                                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                              On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                                                                                              Case Study 7 ndash Presentation

                                                                                                                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                              Case Study 7 ndash Lab Results vs Time

                                                                                                                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                              Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                                                                                              Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                              On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                                                                              Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                              DIC Take Home Messages

                                                                                                                                                                                                                              Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                                                                              Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                                                                              DIC

                                                                                                                                                                                                                              Thank you Questions

                                                                                                                                                                                                                              • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                                                                              • Learning Objectives
                                                                                                                                                                                                                              • Slide Number 3
                                                                                                                                                                                                                              • Slide Number 4
                                                                                                                                                                                                                              • Slide Number 5
                                                                                                                                                                                                                              • Slide Number 6
                                                                                                                                                                                                                              • Slide Number 7
                                                                                                                                                                                                                              • Slide Number 8
                                                                                                                                                                                                                              • Wound Sealing
                                                                                                                                                                                                                              • The Three Steps of Hemostasis
                                                                                                                                                                                                                              • Vessel Wall
                                                                                                                                                                                                                              • Slide Number 12
                                                                                                                                                                                                                              • Slide Number 13
                                                                                                                                                                                                                              • Platelet Structure UnactivatedActivated
                                                                                                                                                                                                                              • Primary Hemostasis
                                                                                                                                                                                                                              • Primary Hemostasis Assays
                                                                                                                                                                                                                              • Slide Number 17
                                                                                                                                                                                                                              • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                                                                              • Slide Number 19
                                                                                                                                                                                                                              • Coagulation factors
                                                                                                                                                                                                                              • Coagulation Assay Mechanisms
                                                                                                                                                                                                                              • Slide Number 22
                                                                                                                                                                                                                              • Fibrin Formation
                                                                                                                                                                                                                              • Slide Number 24
                                                                                                                                                                                                                              • Fibrinolysis Overview
                                                                                                                                                                                                                              • Fibrinolysis Overview
                                                                                                                                                                                                                              • Slide Number 27
                                                                                                                                                                                                                              • Fibrinolysis Releases D-dimers
                                                                                                                                                                                                                              • Basic Pathophysiology of DIC
                                                                                                                                                                                                                              • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                                                                              • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                                                                              • Clinical Conditions Associated With DIC
                                                                                                                                                                                                                              • Frequency of DIC in Selected Disease States
                                                                                                                                                                                                                              • Underlying Diseases in DIC Patients
                                                                                                                                                                                                                              • Slide Number 36
                                                                                                                                                                                                                              • Slide Number 37
                                                                                                                                                                                                                              • Slide Number 38
                                                                                                                                                                                                                              • Slide Number 39
                                                                                                                                                                                                                              • Pathophysiology of DIC
                                                                                                                                                                                                                              • Pathogenesis of DIC in Sepsis
                                                                                                                                                                                                                              • Host Response in Severe Sepsis
                                                                                                                                                                                                                              • Organ Failure in Severe Sepsis
                                                                                                                                                                                                                              • Mechanism of DIC in Organ Failure
                                                                                                                                                                                                                              • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                                                                              • Slide Number 47
                                                                                                                                                                                                                              • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                                                                              • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                                                                              • Mechanism of DIC
                                                                                                                                                                                                                              • Pathophysiology of DIC
                                                                                                                                                                                                                              • Pathophysiology of DIC - Mechanism
                                                                                                                                                                                                                              • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                                                                              • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                                                                              • Pathophysiology of Overt DIC
                                                                                                                                                                                                                              • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                                                                              • Slide Number 57
                                                                                                                                                                                                                              • Slide Number 58
                                                                                                                                                                                                                              • Slide Number 59
                                                                                                                                                                                                                              • Slide Number 60
                                                                                                                                                                                                                              • Slide Number 61
                                                                                                                                                                                                                              • BREAK
                                                                                                                                                                                                                              • Diagnostic and Management Approach for DIC
                                                                                                                                                                                                                              • Diagnosis of DIC
                                                                                                                                                                                                                              • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                                                                              • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                                                                              • Slide Number 67
                                                                                                                                                                                                                              • Slide Number 68
                                                                                                                                                                                                                              • British Journal of Haematology Overt DIC Score
                                                                                                                                                                                                                              • Slide Number 70
                                                                                                                                                                                                                              • Slide Number 71
                                                                                                                                                                                                                              • Slide Number 72
                                                                                                                                                                                                                              • Slide Number 73
                                                                                                                                                                                                                              • DIC Management Goals
                                                                                                                                                                                                                              • DIC Management and Treatment
                                                                                                                                                                                                                              • DIC Management Strategies
                                                                                                                                                                                                                              • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                                                                              • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                                                                              • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                                                                              • D-dimer FDPs and DIC
                                                                                                                                                                                                                              • D-Dimer and FDPs in DIC
                                                                                                                                                                                                                              • Follow Up of DIC State of Disease
                                                                                                                                                                                                                              • FMD-Dimer in DIC Major Differences
                                                                                                                                                                                                                              • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                                                                              • Slide Number 85
                                                                                                                                                                                                                              • Slide Number 86
                                                                                                                                                                                                                              • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                                                                              • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                              • Slide Number 94
                                                                                                                                                                                                                              • Slide Number 95
                                                                                                                                                                                                                              • Slide Number 96
                                                                                                                                                                                                                              • Slide Number 97
                                                                                                                                                                                                                              • Slide Number 98
                                                                                                                                                                                                                              • Slide Number 99
                                                                                                                                                                                                                              • DIC Case Studies
                                                                                                                                                                                                                              • Case Study 1 - Presentation
                                                                                                                                                                                                                              • Case Study 1 ndash Lab Results
                                                                                                                                                                                                                              • Case Study 1 ndash Microscopy
                                                                                                                                                                                                                              • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                                                                              • Slide Number 105
                                                                                                                                                                                                                              • Slide Number 106
                                                                                                                                                                                                                              • Slide Number 107
                                                                                                                                                                                                                              • Slide Number 108
                                                                                                                                                                                                                              • Slide Number 109
                                                                                                                                                                                                                              • Slide Number 110
                                                                                                                                                                                                                              • Slide Number 111
                                                                                                                                                                                                                              • Slide Number 112
                                                                                                                                                                                                                              • Slide Number 113
                                                                                                                                                                                                                              • Slide Number 114
                                                                                                                                                                                                                              • Slide Number 115
                                                                                                                                                                                                                              • Slide Number 116
                                                                                                                                                                                                                              • Slide Number 117
                                                                                                                                                                                                                              • Slide Number 118
                                                                                                                                                                                                                              • Slide Number 119
                                                                                                                                                                                                                              • Slide Number 120
                                                                                                                                                                                                                              • Slide Number 121
                                                                                                                                                                                                                              • Slide Number 122
                                                                                                                                                                                                                              • Slide Number 123
                                                                                                                                                                                                                              • Slide Number 124
                                                                                                                                                                                                                              • Slide Number 125
                                                                                                                                                                                                                              • DIC Take Home Messages
                                                                                                                                                                                                                              • Slide Number 127
                                                                                                                                                                                                                              • Slide Number 128

                                                                                                                                                                                                                                TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L

                                                                                                                                                                                                                                PT 28 sec 113 ndash 146 sec

                                                                                                                                                                                                                                APTT 71 sec 25 ndash 34 sec

                                                                                                                                                                                                                                D-dimer 31 microgmL FEU lt050 microgml FEU

                                                                                                                                                                                                                                Fibrinogen 92 mgdL 150-400 mgdl

                                                                                                                                                                                                                                FV Normal 70-120

                                                                                                                                                                                                                                FVII Normal 55-170

                                                                                                                                                                                                                                FVIII Normal 60-150

                                                                                                                                                                                                                                Protein C Normal 70-130

                                                                                                                                                                                                                                Hb 158 gdL 14-16 gdL

                                                                                                                                                                                                                                WBC 71 times 103mm3 40-11 times 103mm3

                                                                                                                                                                                                                                ALT 60 IUL 0ndash34 IUL

                                                                                                                                                                                                                                AST 47 IUL 0ndash34 IUL

                                                                                                                                                                                                                                BUN 38 mgdL 08-13 mgdL

                                                                                                                                                                                                                                Case Study 4 ndash Lab Results

                                                                                                                                                                                                                                Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                                                                                                                Case Study 4 ndash Diagnosis

                                                                                                                                                                                                                                55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                                                                                                                Case Study 5 ndash Presentation

                                                                                                                                                                                                                                Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                                                Case Study 5 ndash Lab Results and Time Course

                                                                                                                                                                                                                                Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                                                TEST RESULT REFERENCE RANGE

                                                                                                                                                                                                                                Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                                                                                                                PT 215 sec 103 ndash 128 sec

                                                                                                                                                                                                                                APTT 44 sec 26 ndash 36 sec

                                                                                                                                                                                                                                D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                                                                                                                Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                                                                                                                FII FV FVIII Low Not reported (NR)

                                                                                                                                                                                                                                FVII FIX FX vWF Normal NR

                                                                                                                                                                                                                                Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                                                                                                                DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                                                                                                                dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                                                                                                                (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                                                                                                                (D) Illustration demonstrating repair

                                                                                                                                                                                                                                Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                                                                                                                Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                                                29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                                                                                                Case Study 6 ndash Presentation

                                                                                                                                                                                                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                                Case Study 6 ndash Lab Results

                                                                                                                                                                                                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                                TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                                                                                                PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                                                                                                INR 658 1 ndash 125

                                                                                                                                                                                                                                APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                                                                                                D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                                                                                                Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                                                                                                Albumin 28 gdL NR

                                                                                                                                                                                                                                Hb 58 gdL NR

                                                                                                                                                                                                                                LDH 1196 UL NR

                                                                                                                                                                                                                                SGPT 144 IU NR

                                                                                                                                                                                                                                SGOT 88 IU NR

                                                                                                                                                                                                                                Bilirubin 32 mgdL NR

                                                                                                                                                                                                                                DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                                                                                                day postop

                                                                                                                                                                                                                                Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                                                                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                                HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                                                                                                Case Study 6 ndash Discussion

                                                                                                                                                                                                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                                44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                                                                                                Case Study 7 ndash Presentation

                                                                                                                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                                                                                                Case Study 7 ndash Presentation

                                                                                                                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                Case Study 7 ndash Lab Results vs Time

                                                                                                                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                                                                                                Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                                                                                Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                DIC Take Home Messages

                                                                                                                                                                                                                                Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                                                                                Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                                                                                DIC

                                                                                                                                                                                                                                Thank you Questions

                                                                                                                                                                                                                                • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                                                                                • Learning Objectives
                                                                                                                                                                                                                                • Slide Number 3
                                                                                                                                                                                                                                • Slide Number 4
                                                                                                                                                                                                                                • Slide Number 5
                                                                                                                                                                                                                                • Slide Number 6
                                                                                                                                                                                                                                • Slide Number 7
                                                                                                                                                                                                                                • Slide Number 8
                                                                                                                                                                                                                                • Wound Sealing
                                                                                                                                                                                                                                • The Three Steps of Hemostasis
                                                                                                                                                                                                                                • Vessel Wall
                                                                                                                                                                                                                                • Slide Number 12
                                                                                                                                                                                                                                • Slide Number 13
                                                                                                                                                                                                                                • Platelet Structure UnactivatedActivated
                                                                                                                                                                                                                                • Primary Hemostasis
                                                                                                                                                                                                                                • Primary Hemostasis Assays
                                                                                                                                                                                                                                • Slide Number 17
                                                                                                                                                                                                                                • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                                                                                • Slide Number 19
                                                                                                                                                                                                                                • Coagulation factors
                                                                                                                                                                                                                                • Coagulation Assay Mechanisms
                                                                                                                                                                                                                                • Slide Number 22
                                                                                                                                                                                                                                • Fibrin Formation
                                                                                                                                                                                                                                • Slide Number 24
                                                                                                                                                                                                                                • Fibrinolysis Overview
                                                                                                                                                                                                                                • Fibrinolysis Overview
                                                                                                                                                                                                                                • Slide Number 27
                                                                                                                                                                                                                                • Fibrinolysis Releases D-dimers
                                                                                                                                                                                                                                • Basic Pathophysiology of DIC
                                                                                                                                                                                                                                • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                                                                                • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                                                                                • Clinical Conditions Associated With DIC
                                                                                                                                                                                                                                • Frequency of DIC in Selected Disease States
                                                                                                                                                                                                                                • Underlying Diseases in DIC Patients
                                                                                                                                                                                                                                • Slide Number 36
                                                                                                                                                                                                                                • Slide Number 37
                                                                                                                                                                                                                                • Slide Number 38
                                                                                                                                                                                                                                • Slide Number 39
                                                                                                                                                                                                                                • Pathophysiology of DIC
                                                                                                                                                                                                                                • Pathogenesis of DIC in Sepsis
                                                                                                                                                                                                                                • Host Response in Severe Sepsis
                                                                                                                                                                                                                                • Organ Failure in Severe Sepsis
                                                                                                                                                                                                                                • Mechanism of DIC in Organ Failure
                                                                                                                                                                                                                                • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                                                                                • Slide Number 47
                                                                                                                                                                                                                                • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                                                                                • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                                                                                • Mechanism of DIC
                                                                                                                                                                                                                                • Pathophysiology of DIC
                                                                                                                                                                                                                                • Pathophysiology of DIC - Mechanism
                                                                                                                                                                                                                                • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                                                                                • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                                                                                • Pathophysiology of Overt DIC
                                                                                                                                                                                                                                • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                                                                                • Slide Number 57
                                                                                                                                                                                                                                • Slide Number 58
                                                                                                                                                                                                                                • Slide Number 59
                                                                                                                                                                                                                                • Slide Number 60
                                                                                                                                                                                                                                • Slide Number 61
                                                                                                                                                                                                                                • BREAK
                                                                                                                                                                                                                                • Diagnostic and Management Approach for DIC
                                                                                                                                                                                                                                • Diagnosis of DIC
                                                                                                                                                                                                                                • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                                                                                • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                                                                                • Slide Number 67
                                                                                                                                                                                                                                • Slide Number 68
                                                                                                                                                                                                                                • British Journal of Haematology Overt DIC Score
                                                                                                                                                                                                                                • Slide Number 70
                                                                                                                                                                                                                                • Slide Number 71
                                                                                                                                                                                                                                • Slide Number 72
                                                                                                                                                                                                                                • Slide Number 73
                                                                                                                                                                                                                                • DIC Management Goals
                                                                                                                                                                                                                                • DIC Management and Treatment
                                                                                                                                                                                                                                • DIC Management Strategies
                                                                                                                                                                                                                                • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                                                                                • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                                                                                • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                                                                                • D-dimer FDPs and DIC
                                                                                                                                                                                                                                • D-Dimer and FDPs in DIC
                                                                                                                                                                                                                                • Follow Up of DIC State of Disease
                                                                                                                                                                                                                                • FMD-Dimer in DIC Major Differences
                                                                                                                                                                                                                                • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                                                                                • Slide Number 85
                                                                                                                                                                                                                                • Slide Number 86
                                                                                                                                                                                                                                • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                                                                                • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                • Slide Number 94
                                                                                                                                                                                                                                • Slide Number 95
                                                                                                                                                                                                                                • Slide Number 96
                                                                                                                                                                                                                                • Slide Number 97
                                                                                                                                                                                                                                • Slide Number 98
                                                                                                                                                                                                                                • Slide Number 99
                                                                                                                                                                                                                                • DIC Case Studies
                                                                                                                                                                                                                                • Case Study 1 - Presentation
                                                                                                                                                                                                                                • Case Study 1 ndash Lab Results
                                                                                                                                                                                                                                • Case Study 1 ndash Microscopy
                                                                                                                                                                                                                                • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                                                                                • Slide Number 105
                                                                                                                                                                                                                                • Slide Number 106
                                                                                                                                                                                                                                • Slide Number 107
                                                                                                                                                                                                                                • Slide Number 108
                                                                                                                                                                                                                                • Slide Number 109
                                                                                                                                                                                                                                • Slide Number 110
                                                                                                                                                                                                                                • Slide Number 111
                                                                                                                                                                                                                                • Slide Number 112
                                                                                                                                                                                                                                • Slide Number 113
                                                                                                                                                                                                                                • Slide Number 114
                                                                                                                                                                                                                                • Slide Number 115
                                                                                                                                                                                                                                • Slide Number 116
                                                                                                                                                                                                                                • Slide Number 117
                                                                                                                                                                                                                                • Slide Number 118
                                                                                                                                                                                                                                • Slide Number 119
                                                                                                                                                                                                                                • Slide Number 120
                                                                                                                                                                                                                                • Slide Number 121
                                                                                                                                                                                                                                • Slide Number 122
                                                                                                                                                                                                                                • Slide Number 123
                                                                                                                                                                                                                                • Slide Number 124
                                                                                                                                                                                                                                • Slide Number 125
                                                                                                                                                                                                                                • DIC Take Home Messages
                                                                                                                                                                                                                                • Slide Number 127
                                                                                                                                                                                                                                • Slide Number 128

                                                                                                                                                                                                                                  Lyme disease with DICProvide antibiotics with supportive measures

                                                                                                                                                                                                                                  Case Study 4 ndash Diagnosis

                                                                                                                                                                                                                                  55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                                                                                                                  Case Study 5 ndash Presentation

                                                                                                                                                                                                                                  Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                                                  Case Study 5 ndash Lab Results and Time Course

                                                                                                                                                                                                                                  Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                                                  TEST RESULT REFERENCE RANGE

                                                                                                                                                                                                                                  Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                                                                                                                  PT 215 sec 103 ndash 128 sec

                                                                                                                                                                                                                                  APTT 44 sec 26 ndash 36 sec

                                                                                                                                                                                                                                  D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                                                                                                                  Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                                                                                                                  FII FV FVIII Low Not reported (NR)

                                                                                                                                                                                                                                  FVII FIX FX vWF Normal NR

                                                                                                                                                                                                                                  Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                                                                                                                  DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                                                                                                                  dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                                                                                                                  (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                                                                                                                  (D) Illustration demonstrating repair

                                                                                                                                                                                                                                  Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                                                                                                                  Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                                                  29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                                                                                                  Case Study 6 ndash Presentation

                                                                                                                                                                                                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                                  Case Study 6 ndash Lab Results

                                                                                                                                                                                                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                                  TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                                                                                                  PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                                                                                                  INR 658 1 ndash 125

                                                                                                                                                                                                                                  APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                                                                                                  D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                                                                                                  Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                                                                                                  Albumin 28 gdL NR

                                                                                                                                                                                                                                  Hb 58 gdL NR

                                                                                                                                                                                                                                  LDH 1196 UL NR

                                                                                                                                                                                                                                  SGPT 144 IU NR

                                                                                                                                                                                                                                  SGOT 88 IU NR

                                                                                                                                                                                                                                  Bilirubin 32 mgdL NR

                                                                                                                                                                                                                                  DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                                                                                                  day postop

                                                                                                                                                                                                                                  Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                                                                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                                  HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                                                                                                  Case Study 6 ndash Discussion

                                                                                                                                                                                                                                  Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                                  44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                                                                                                  Case Study 7 ndash Presentation

                                                                                                                                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                  On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                                                                                                  Case Study 7 ndash Presentation

                                                                                                                                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                  Case Study 7 ndash Lab Results vs Time

                                                                                                                                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                  Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                                                                                                  Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                  On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                                                                                  Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                  DIC Take Home Messages

                                                                                                                                                                                                                                  Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                                                                                  Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                                                                                  DIC

                                                                                                                                                                                                                                  Thank you Questions

                                                                                                                                                                                                                                  • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                                                                                  • Learning Objectives
                                                                                                                                                                                                                                  • Slide Number 3
                                                                                                                                                                                                                                  • Slide Number 4
                                                                                                                                                                                                                                  • Slide Number 5
                                                                                                                                                                                                                                  • Slide Number 6
                                                                                                                                                                                                                                  • Slide Number 7
                                                                                                                                                                                                                                  • Slide Number 8
                                                                                                                                                                                                                                  • Wound Sealing
                                                                                                                                                                                                                                  • The Three Steps of Hemostasis
                                                                                                                                                                                                                                  • Vessel Wall
                                                                                                                                                                                                                                  • Slide Number 12
                                                                                                                                                                                                                                  • Slide Number 13
                                                                                                                                                                                                                                  • Platelet Structure UnactivatedActivated
                                                                                                                                                                                                                                  • Primary Hemostasis
                                                                                                                                                                                                                                  • Primary Hemostasis Assays
                                                                                                                                                                                                                                  • Slide Number 17
                                                                                                                                                                                                                                  • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                                                                                  • Slide Number 19
                                                                                                                                                                                                                                  • Coagulation factors
                                                                                                                                                                                                                                  • Coagulation Assay Mechanisms
                                                                                                                                                                                                                                  • Slide Number 22
                                                                                                                                                                                                                                  • Fibrin Formation
                                                                                                                                                                                                                                  • Slide Number 24
                                                                                                                                                                                                                                  • Fibrinolysis Overview
                                                                                                                                                                                                                                  • Fibrinolysis Overview
                                                                                                                                                                                                                                  • Slide Number 27
                                                                                                                                                                                                                                  • Fibrinolysis Releases D-dimers
                                                                                                                                                                                                                                  • Basic Pathophysiology of DIC
                                                                                                                                                                                                                                  • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                                                                                  • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                                                                                  • Clinical Conditions Associated With DIC
                                                                                                                                                                                                                                  • Frequency of DIC in Selected Disease States
                                                                                                                                                                                                                                  • Underlying Diseases in DIC Patients
                                                                                                                                                                                                                                  • Slide Number 36
                                                                                                                                                                                                                                  • Slide Number 37
                                                                                                                                                                                                                                  • Slide Number 38
                                                                                                                                                                                                                                  • Slide Number 39
                                                                                                                                                                                                                                  • Pathophysiology of DIC
                                                                                                                                                                                                                                  • Pathogenesis of DIC in Sepsis
                                                                                                                                                                                                                                  • Host Response in Severe Sepsis
                                                                                                                                                                                                                                  • Organ Failure in Severe Sepsis
                                                                                                                                                                                                                                  • Mechanism of DIC in Organ Failure
                                                                                                                                                                                                                                  • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                                                                                  • Slide Number 47
                                                                                                                                                                                                                                  • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                                                                                  • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                                                                                  • Mechanism of DIC
                                                                                                                                                                                                                                  • Pathophysiology of DIC
                                                                                                                                                                                                                                  • Pathophysiology of DIC - Mechanism
                                                                                                                                                                                                                                  • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                                                                                  • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                                                                                  • Pathophysiology of Overt DIC
                                                                                                                                                                                                                                  • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                                                                                  • Slide Number 57
                                                                                                                                                                                                                                  • Slide Number 58
                                                                                                                                                                                                                                  • Slide Number 59
                                                                                                                                                                                                                                  • Slide Number 60
                                                                                                                                                                                                                                  • Slide Number 61
                                                                                                                                                                                                                                  • BREAK
                                                                                                                                                                                                                                  • Diagnostic and Management Approach for DIC
                                                                                                                                                                                                                                  • Diagnosis of DIC
                                                                                                                                                                                                                                  • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                                                                                  • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                                                                                  • Slide Number 67
                                                                                                                                                                                                                                  • Slide Number 68
                                                                                                                                                                                                                                  • British Journal of Haematology Overt DIC Score
                                                                                                                                                                                                                                  • Slide Number 70
                                                                                                                                                                                                                                  • Slide Number 71
                                                                                                                                                                                                                                  • Slide Number 72
                                                                                                                                                                                                                                  • Slide Number 73
                                                                                                                                                                                                                                  • DIC Management Goals
                                                                                                                                                                                                                                  • DIC Management and Treatment
                                                                                                                                                                                                                                  • DIC Management Strategies
                                                                                                                                                                                                                                  • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                                                                                  • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                                                                                  • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                                                                                  • D-dimer FDPs and DIC
                                                                                                                                                                                                                                  • D-Dimer and FDPs in DIC
                                                                                                                                                                                                                                  • Follow Up of DIC State of Disease
                                                                                                                                                                                                                                  • FMD-Dimer in DIC Major Differences
                                                                                                                                                                                                                                  • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                                                                                  • Slide Number 85
                                                                                                                                                                                                                                  • Slide Number 86
                                                                                                                                                                                                                                  • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                                                                                  • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                  • Slide Number 94
                                                                                                                                                                                                                                  • Slide Number 95
                                                                                                                                                                                                                                  • Slide Number 96
                                                                                                                                                                                                                                  • Slide Number 97
                                                                                                                                                                                                                                  • Slide Number 98
                                                                                                                                                                                                                                  • Slide Number 99
                                                                                                                                                                                                                                  • DIC Case Studies
                                                                                                                                                                                                                                  • Case Study 1 - Presentation
                                                                                                                                                                                                                                  • Case Study 1 ndash Lab Results
                                                                                                                                                                                                                                  • Case Study 1 ndash Microscopy
                                                                                                                                                                                                                                  • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                                                                                  • Slide Number 105
                                                                                                                                                                                                                                  • Slide Number 106
                                                                                                                                                                                                                                  • Slide Number 107
                                                                                                                                                                                                                                  • Slide Number 108
                                                                                                                                                                                                                                  • Slide Number 109
                                                                                                                                                                                                                                  • Slide Number 110
                                                                                                                                                                                                                                  • Slide Number 111
                                                                                                                                                                                                                                  • Slide Number 112
                                                                                                                                                                                                                                  • Slide Number 113
                                                                                                                                                                                                                                  • Slide Number 114
                                                                                                                                                                                                                                  • Slide Number 115
                                                                                                                                                                                                                                  • Slide Number 116
                                                                                                                                                                                                                                  • Slide Number 117
                                                                                                                                                                                                                                  • Slide Number 118
                                                                                                                                                                                                                                  • Slide Number 119
                                                                                                                                                                                                                                  • Slide Number 120
                                                                                                                                                                                                                                  • Slide Number 121
                                                                                                                                                                                                                                  • Slide Number 122
                                                                                                                                                                                                                                  • Slide Number 123
                                                                                                                                                                                                                                  • Slide Number 124
                                                                                                                                                                                                                                  • Slide Number 125
                                                                                                                                                                                                                                  • DIC Take Home Messages
                                                                                                                                                                                                                                  • Slide Number 127
                                                                                                                                                                                                                                  • Slide Number 128

                                                                                                                                                                                                                                    55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis

                                                                                                                                                                                                                                    Case Study 5 ndash Presentation

                                                                                                                                                                                                                                    Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                                                    Case Study 5 ndash Lab Results and Time Course

                                                                                                                                                                                                                                    Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                                                    TEST RESULT REFERENCE RANGE

                                                                                                                                                                                                                                    Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                                                                                                                    PT 215 sec 103 ndash 128 sec

                                                                                                                                                                                                                                    APTT 44 sec 26 ndash 36 sec

                                                                                                                                                                                                                                    D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                                                                                                                    Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                                                                                                                    FII FV FVIII Low Not reported (NR)

                                                                                                                                                                                                                                    FVII FIX FX vWF Normal NR

                                                                                                                                                                                                                                    Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                                                                                                                    DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                                                                                                                    dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                                                                                                                    (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                                                                                                                    (D) Illustration demonstrating repair

                                                                                                                                                                                                                                    Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                                                                                                                    Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                                                    29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                                                                                                    Case Study 6 ndash Presentation

                                                                                                                                                                                                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                                    Case Study 6 ndash Lab Results

                                                                                                                                                                                                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                                    TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                                                                                                    PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                                                                                                    INR 658 1 ndash 125

                                                                                                                                                                                                                                    APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                                                                                                    D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                                                                                                    Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                                                                                                    Albumin 28 gdL NR

                                                                                                                                                                                                                                    Hb 58 gdL NR

                                                                                                                                                                                                                                    LDH 1196 UL NR

                                                                                                                                                                                                                                    SGPT 144 IU NR

                                                                                                                                                                                                                                    SGOT 88 IU NR

                                                                                                                                                                                                                                    Bilirubin 32 mgdL NR

                                                                                                                                                                                                                                    DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                                                                                                    day postop

                                                                                                                                                                                                                                    Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                                                                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                                    HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                                                                                                    Case Study 6 ndash Discussion

                                                                                                                                                                                                                                    Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                                    44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                                                                                                    Case Study 7 ndash Presentation

                                                                                                                                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                    On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                                                                                                    Case Study 7 ndash Presentation

                                                                                                                                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                    Case Study 7 ndash Lab Results vs Time

                                                                                                                                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                    Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                                                                                                    Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                    On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                                                                                    Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                    DIC Take Home Messages

                                                                                                                                                                                                                                    Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                                                                                    Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                                                                                    DIC

                                                                                                                                                                                                                                    Thank you Questions

                                                                                                                                                                                                                                    • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                                                                                    • Learning Objectives
                                                                                                                                                                                                                                    • Slide Number 3
                                                                                                                                                                                                                                    • Slide Number 4
                                                                                                                                                                                                                                    • Slide Number 5
                                                                                                                                                                                                                                    • Slide Number 6
                                                                                                                                                                                                                                    • Slide Number 7
                                                                                                                                                                                                                                    • Slide Number 8
                                                                                                                                                                                                                                    • Wound Sealing
                                                                                                                                                                                                                                    • The Three Steps of Hemostasis
                                                                                                                                                                                                                                    • Vessel Wall
                                                                                                                                                                                                                                    • Slide Number 12
                                                                                                                                                                                                                                    • Slide Number 13
                                                                                                                                                                                                                                    • Platelet Structure UnactivatedActivated
                                                                                                                                                                                                                                    • Primary Hemostasis
                                                                                                                                                                                                                                    • Primary Hemostasis Assays
                                                                                                                                                                                                                                    • Slide Number 17
                                                                                                                                                                                                                                    • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                                                                                    • Slide Number 19
                                                                                                                                                                                                                                    • Coagulation factors
                                                                                                                                                                                                                                    • Coagulation Assay Mechanisms
                                                                                                                                                                                                                                    • Slide Number 22
                                                                                                                                                                                                                                    • Fibrin Formation
                                                                                                                                                                                                                                    • Slide Number 24
                                                                                                                                                                                                                                    • Fibrinolysis Overview
                                                                                                                                                                                                                                    • Fibrinolysis Overview
                                                                                                                                                                                                                                    • Slide Number 27
                                                                                                                                                                                                                                    • Fibrinolysis Releases D-dimers
                                                                                                                                                                                                                                    • Basic Pathophysiology of DIC
                                                                                                                                                                                                                                    • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                                                                                    • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                                                                                    • Clinical Conditions Associated With DIC
                                                                                                                                                                                                                                    • Frequency of DIC in Selected Disease States
                                                                                                                                                                                                                                    • Underlying Diseases in DIC Patients
                                                                                                                                                                                                                                    • Slide Number 36
                                                                                                                                                                                                                                    • Slide Number 37
                                                                                                                                                                                                                                    • Slide Number 38
                                                                                                                                                                                                                                    • Slide Number 39
                                                                                                                                                                                                                                    • Pathophysiology of DIC
                                                                                                                                                                                                                                    • Pathogenesis of DIC in Sepsis
                                                                                                                                                                                                                                    • Host Response in Severe Sepsis
                                                                                                                                                                                                                                    • Organ Failure in Severe Sepsis
                                                                                                                                                                                                                                    • Mechanism of DIC in Organ Failure
                                                                                                                                                                                                                                    • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                                                                                    • Slide Number 47
                                                                                                                                                                                                                                    • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                                                                                    • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                                                                                    • Mechanism of DIC
                                                                                                                                                                                                                                    • Pathophysiology of DIC
                                                                                                                                                                                                                                    • Pathophysiology of DIC - Mechanism
                                                                                                                                                                                                                                    • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                                                                                    • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                                                                                    • Pathophysiology of Overt DIC
                                                                                                                                                                                                                                    • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                                                                                    • Slide Number 57
                                                                                                                                                                                                                                    • Slide Number 58
                                                                                                                                                                                                                                    • Slide Number 59
                                                                                                                                                                                                                                    • Slide Number 60
                                                                                                                                                                                                                                    • Slide Number 61
                                                                                                                                                                                                                                    • BREAK
                                                                                                                                                                                                                                    • Diagnostic and Management Approach for DIC
                                                                                                                                                                                                                                    • Diagnosis of DIC
                                                                                                                                                                                                                                    • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                                                                                    • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                                                                                    • Slide Number 67
                                                                                                                                                                                                                                    • Slide Number 68
                                                                                                                                                                                                                                    • British Journal of Haematology Overt DIC Score
                                                                                                                                                                                                                                    • Slide Number 70
                                                                                                                                                                                                                                    • Slide Number 71
                                                                                                                                                                                                                                    • Slide Number 72
                                                                                                                                                                                                                                    • Slide Number 73
                                                                                                                                                                                                                                    • DIC Management Goals
                                                                                                                                                                                                                                    • DIC Management and Treatment
                                                                                                                                                                                                                                    • DIC Management Strategies
                                                                                                                                                                                                                                    • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                                                                                    • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                                                                                    • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                                                                                    • D-dimer FDPs and DIC
                                                                                                                                                                                                                                    • D-Dimer and FDPs in DIC
                                                                                                                                                                                                                                    • Follow Up of DIC State of Disease
                                                                                                                                                                                                                                    • FMD-Dimer in DIC Major Differences
                                                                                                                                                                                                                                    • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                                                                                    • Slide Number 85
                                                                                                                                                                                                                                    • Slide Number 86
                                                                                                                                                                                                                                    • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                                                                                    • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                    • Slide Number 94
                                                                                                                                                                                                                                    • Slide Number 95
                                                                                                                                                                                                                                    • Slide Number 96
                                                                                                                                                                                                                                    • Slide Number 97
                                                                                                                                                                                                                                    • Slide Number 98
                                                                                                                                                                                                                                    • Slide Number 99
                                                                                                                                                                                                                                    • DIC Case Studies
                                                                                                                                                                                                                                    • Case Study 1 - Presentation
                                                                                                                                                                                                                                    • Case Study 1 ndash Lab Results
                                                                                                                                                                                                                                    • Case Study 1 ndash Microscopy
                                                                                                                                                                                                                                    • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                                                                                    • Slide Number 105
                                                                                                                                                                                                                                    • Slide Number 106
                                                                                                                                                                                                                                    • Slide Number 107
                                                                                                                                                                                                                                    • Slide Number 108
                                                                                                                                                                                                                                    • Slide Number 109
                                                                                                                                                                                                                                    • Slide Number 110
                                                                                                                                                                                                                                    • Slide Number 111
                                                                                                                                                                                                                                    • Slide Number 112
                                                                                                                                                                                                                                    • Slide Number 113
                                                                                                                                                                                                                                    • Slide Number 114
                                                                                                                                                                                                                                    • Slide Number 115
                                                                                                                                                                                                                                    • Slide Number 116
                                                                                                                                                                                                                                    • Slide Number 117
                                                                                                                                                                                                                                    • Slide Number 118
                                                                                                                                                                                                                                    • Slide Number 119
                                                                                                                                                                                                                                    • Slide Number 120
                                                                                                                                                                                                                                    • Slide Number 121
                                                                                                                                                                                                                                    • Slide Number 122
                                                                                                                                                                                                                                    • Slide Number 123
                                                                                                                                                                                                                                    • Slide Number 124
                                                                                                                                                                                                                                    • Slide Number 125
                                                                                                                                                                                                                                    • DIC Take Home Messages
                                                                                                                                                                                                                                    • Slide Number 127
                                                                                                                                                                                                                                    • Slide Number 128

                                                                                                                                                                                                                                      Case Study 5 ndash Lab Results and Time Course

                                                                                                                                                                                                                                      Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                                                      TEST RESULT REFERENCE RANGE

                                                                                                                                                                                                                                      Platelet count 33 x 109L 150-450 x 109L

                                                                                                                                                                                                                                      PT 215 sec 103 ndash 128 sec

                                                                                                                                                                                                                                      APTT 44 sec 26 ndash 36 sec

                                                                                                                                                                                                                                      D-dimer 20 microgmL FEU lt025 microgml FEU

                                                                                                                                                                                                                                      Fibrinogen 34 mgdL 200-375 mgdl

                                                                                                                                                                                                                                      FII FV FVIII Low Not reported (NR)

                                                                                                                                                                                                                                      FVII FIX FX vWF Normal NR

                                                                                                                                                                                                                                      Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)

                                                                                                                                                                                                                                      DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                                                                                                                      dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                                                                                                                      (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                                                                                                                      (D) Illustration demonstrating repair

                                                                                                                                                                                                                                      Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                                                                                                                      Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                                                      29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                                                                                                      Case Study 6 ndash Presentation

                                                                                                                                                                                                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                                      Case Study 6 ndash Lab Results

                                                                                                                                                                                                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                                      TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                                                                                                      PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                                                                                                      INR 658 1 ndash 125

                                                                                                                                                                                                                                      APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                                                                                                      D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                                                                                                      Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                                                                                                      Albumin 28 gdL NR

                                                                                                                                                                                                                                      Hb 58 gdL NR

                                                                                                                                                                                                                                      LDH 1196 UL NR

                                                                                                                                                                                                                                      SGPT 144 IU NR

                                                                                                                                                                                                                                      SGOT 88 IU NR

                                                                                                                                                                                                                                      Bilirubin 32 mgdL NR

                                                                                                                                                                                                                                      DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                                                                                                      day postop

                                                                                                                                                                                                                                      Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                                                                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                                      HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                                                                                                      Case Study 6 ndash Discussion

                                                                                                                                                                                                                                      Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                                      44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                                                                                                      Case Study 7 ndash Presentation

                                                                                                                                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                      On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                                                                                                      Case Study 7 ndash Presentation

                                                                                                                                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                      Case Study 7 ndash Lab Results vs Time

                                                                                                                                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                      Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                                                                                                      Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                      On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                                                                                      Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                      DIC Take Home Messages

                                                                                                                                                                                                                                      Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                                                                                      Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                                                                                      DIC

                                                                                                                                                                                                                                      Thank you Questions

                                                                                                                                                                                                                                      • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                                                                                      • Learning Objectives
                                                                                                                                                                                                                                      • Slide Number 3
                                                                                                                                                                                                                                      • Slide Number 4
                                                                                                                                                                                                                                      • Slide Number 5
                                                                                                                                                                                                                                      • Slide Number 6
                                                                                                                                                                                                                                      • Slide Number 7
                                                                                                                                                                                                                                      • Slide Number 8
                                                                                                                                                                                                                                      • Wound Sealing
                                                                                                                                                                                                                                      • The Three Steps of Hemostasis
                                                                                                                                                                                                                                      • Vessel Wall
                                                                                                                                                                                                                                      • Slide Number 12
                                                                                                                                                                                                                                      • Slide Number 13
                                                                                                                                                                                                                                      • Platelet Structure UnactivatedActivated
                                                                                                                                                                                                                                      • Primary Hemostasis
                                                                                                                                                                                                                                      • Primary Hemostasis Assays
                                                                                                                                                                                                                                      • Slide Number 17
                                                                                                                                                                                                                                      • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                                                                                      • Slide Number 19
                                                                                                                                                                                                                                      • Coagulation factors
                                                                                                                                                                                                                                      • Coagulation Assay Mechanisms
                                                                                                                                                                                                                                      • Slide Number 22
                                                                                                                                                                                                                                      • Fibrin Formation
                                                                                                                                                                                                                                      • Slide Number 24
                                                                                                                                                                                                                                      • Fibrinolysis Overview
                                                                                                                                                                                                                                      • Fibrinolysis Overview
                                                                                                                                                                                                                                      • Slide Number 27
                                                                                                                                                                                                                                      • Fibrinolysis Releases D-dimers
                                                                                                                                                                                                                                      • Basic Pathophysiology of DIC
                                                                                                                                                                                                                                      • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                                                                                      • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                                                                                      • Clinical Conditions Associated With DIC
                                                                                                                                                                                                                                      • Frequency of DIC in Selected Disease States
                                                                                                                                                                                                                                      • Underlying Diseases in DIC Patients
                                                                                                                                                                                                                                      • Slide Number 36
                                                                                                                                                                                                                                      • Slide Number 37
                                                                                                                                                                                                                                      • Slide Number 38
                                                                                                                                                                                                                                      • Slide Number 39
                                                                                                                                                                                                                                      • Pathophysiology of DIC
                                                                                                                                                                                                                                      • Pathogenesis of DIC in Sepsis
                                                                                                                                                                                                                                      • Host Response in Severe Sepsis
                                                                                                                                                                                                                                      • Organ Failure in Severe Sepsis
                                                                                                                                                                                                                                      • Mechanism of DIC in Organ Failure
                                                                                                                                                                                                                                      • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                                                                                      • Slide Number 47
                                                                                                                                                                                                                                      • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                                                                                      • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                                                                                      • Mechanism of DIC
                                                                                                                                                                                                                                      • Pathophysiology of DIC
                                                                                                                                                                                                                                      • Pathophysiology of DIC - Mechanism
                                                                                                                                                                                                                                      • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                                                                                      • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                                                                                      • Pathophysiology of Overt DIC
                                                                                                                                                                                                                                      • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                                                                                      • Slide Number 57
                                                                                                                                                                                                                                      • Slide Number 58
                                                                                                                                                                                                                                      • Slide Number 59
                                                                                                                                                                                                                                      • Slide Number 60
                                                                                                                                                                                                                                      • Slide Number 61
                                                                                                                                                                                                                                      • BREAK
                                                                                                                                                                                                                                      • Diagnostic and Management Approach for DIC
                                                                                                                                                                                                                                      • Diagnosis of DIC
                                                                                                                                                                                                                                      • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                                                                                      • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                                                                                      • Slide Number 67
                                                                                                                                                                                                                                      • Slide Number 68
                                                                                                                                                                                                                                      • British Journal of Haematology Overt DIC Score
                                                                                                                                                                                                                                      • Slide Number 70
                                                                                                                                                                                                                                      • Slide Number 71
                                                                                                                                                                                                                                      • Slide Number 72
                                                                                                                                                                                                                                      • Slide Number 73
                                                                                                                                                                                                                                      • DIC Management Goals
                                                                                                                                                                                                                                      • DIC Management and Treatment
                                                                                                                                                                                                                                      • DIC Management Strategies
                                                                                                                                                                                                                                      • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                                                                                      • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                                                                                      • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                                                                                      • D-dimer FDPs and DIC
                                                                                                                                                                                                                                      • D-Dimer and FDPs in DIC
                                                                                                                                                                                                                                      • Follow Up of DIC State of Disease
                                                                                                                                                                                                                                      • FMD-Dimer in DIC Major Differences
                                                                                                                                                                                                                                      • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                                                                                      • Slide Number 85
                                                                                                                                                                                                                                      • Slide Number 86
                                                                                                                                                                                                                                      • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                                                                                      • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                      • Slide Number 94
                                                                                                                                                                                                                                      • Slide Number 95
                                                                                                                                                                                                                                      • Slide Number 96
                                                                                                                                                                                                                                      • Slide Number 97
                                                                                                                                                                                                                                      • Slide Number 98
                                                                                                                                                                                                                                      • Slide Number 99
                                                                                                                                                                                                                                      • DIC Case Studies
                                                                                                                                                                                                                                      • Case Study 1 - Presentation
                                                                                                                                                                                                                                      • Case Study 1 ndash Lab Results
                                                                                                                                                                                                                                      • Case Study 1 ndash Microscopy
                                                                                                                                                                                                                                      • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                                                                                      • Slide Number 105
                                                                                                                                                                                                                                      • Slide Number 106
                                                                                                                                                                                                                                      • Slide Number 107
                                                                                                                                                                                                                                      • Slide Number 108
                                                                                                                                                                                                                                      • Slide Number 109
                                                                                                                                                                                                                                      • Slide Number 110
                                                                                                                                                                                                                                      • Slide Number 111
                                                                                                                                                                                                                                      • Slide Number 112
                                                                                                                                                                                                                                      • Slide Number 113
                                                                                                                                                                                                                                      • Slide Number 114
                                                                                                                                                                                                                                      • Slide Number 115
                                                                                                                                                                                                                                      • Slide Number 116
                                                                                                                                                                                                                                      • Slide Number 117
                                                                                                                                                                                                                                      • Slide Number 118
                                                                                                                                                                                                                                      • Slide Number 119
                                                                                                                                                                                                                                      • Slide Number 120
                                                                                                                                                                                                                                      • Slide Number 121
                                                                                                                                                                                                                                      • Slide Number 122
                                                                                                                                                                                                                                      • Slide Number 123
                                                                                                                                                                                                                                      • Slide Number 124
                                                                                                                                                                                                                                      • Slide Number 125
                                                                                                                                                                                                                                      • DIC Take Home Messages
                                                                                                                                                                                                                                      • Slide Number 127
                                                                                                                                                                                                                                      • Slide Number 128

                                                                                                                                                                                                                                        DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic

                                                                                                                                                                                                                                        dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR

                                                                                                                                                                                                                                        (C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen

                                                                                                                                                                                                                                        (D) Illustration demonstrating repair

                                                                                                                                                                                                                                        Case Study 5 ndash Diagnosis and Treatment

                                                                                                                                                                                                                                        Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41

                                                                                                                                                                                                                                        29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                                                                                                        Case Study 6 ndash Presentation

                                                                                                                                                                                                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                                        Case Study 6 ndash Lab Results

                                                                                                                                                                                                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                                        TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                                                                                                        PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                                                                                                        INR 658 1 ndash 125

                                                                                                                                                                                                                                        APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                                                                                                        D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                                                                                                        Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                                                                                                        Albumin 28 gdL NR

                                                                                                                                                                                                                                        Hb 58 gdL NR

                                                                                                                                                                                                                                        LDH 1196 UL NR

                                                                                                                                                                                                                                        SGPT 144 IU NR

                                                                                                                                                                                                                                        SGOT 88 IU NR

                                                                                                                                                                                                                                        Bilirubin 32 mgdL NR

                                                                                                                                                                                                                                        DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                                                                                                        day postop

                                                                                                                                                                                                                                        Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                                                                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                                        HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                                                                                                        Case Study 6 ndash Discussion

                                                                                                                                                                                                                                        Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                                        44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                                                                                                        Case Study 7 ndash Presentation

                                                                                                                                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                        On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                                                                                                        Case Study 7 ndash Presentation

                                                                                                                                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                        Case Study 7 ndash Lab Results vs Time

                                                                                                                                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                        Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                                                                                                        Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                        On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                                                                                        Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                        DIC Take Home Messages

                                                                                                                                                                                                                                        Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                                                                                        Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                                                                                        DIC

                                                                                                                                                                                                                                        Thank you Questions

                                                                                                                                                                                                                                        • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                                                                                        • Learning Objectives
                                                                                                                                                                                                                                        • Slide Number 3
                                                                                                                                                                                                                                        • Slide Number 4
                                                                                                                                                                                                                                        • Slide Number 5
                                                                                                                                                                                                                                        • Slide Number 6
                                                                                                                                                                                                                                        • Slide Number 7
                                                                                                                                                                                                                                        • Slide Number 8
                                                                                                                                                                                                                                        • Wound Sealing
                                                                                                                                                                                                                                        • The Three Steps of Hemostasis
                                                                                                                                                                                                                                        • Vessel Wall
                                                                                                                                                                                                                                        • Slide Number 12
                                                                                                                                                                                                                                        • Slide Number 13
                                                                                                                                                                                                                                        • Platelet Structure UnactivatedActivated
                                                                                                                                                                                                                                        • Primary Hemostasis
                                                                                                                                                                                                                                        • Primary Hemostasis Assays
                                                                                                                                                                                                                                        • Slide Number 17
                                                                                                                                                                                                                                        • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                                                                                        • Slide Number 19
                                                                                                                                                                                                                                        • Coagulation factors
                                                                                                                                                                                                                                        • Coagulation Assay Mechanisms
                                                                                                                                                                                                                                        • Slide Number 22
                                                                                                                                                                                                                                        • Fibrin Formation
                                                                                                                                                                                                                                        • Slide Number 24
                                                                                                                                                                                                                                        • Fibrinolysis Overview
                                                                                                                                                                                                                                        • Fibrinolysis Overview
                                                                                                                                                                                                                                        • Slide Number 27
                                                                                                                                                                                                                                        • Fibrinolysis Releases D-dimers
                                                                                                                                                                                                                                        • Basic Pathophysiology of DIC
                                                                                                                                                                                                                                        • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                                                                                        • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                                                                                        • Clinical Conditions Associated With DIC
                                                                                                                                                                                                                                        • Frequency of DIC in Selected Disease States
                                                                                                                                                                                                                                        • Underlying Diseases in DIC Patients
                                                                                                                                                                                                                                        • Slide Number 36
                                                                                                                                                                                                                                        • Slide Number 37
                                                                                                                                                                                                                                        • Slide Number 38
                                                                                                                                                                                                                                        • Slide Number 39
                                                                                                                                                                                                                                        • Pathophysiology of DIC
                                                                                                                                                                                                                                        • Pathogenesis of DIC in Sepsis
                                                                                                                                                                                                                                        • Host Response in Severe Sepsis
                                                                                                                                                                                                                                        • Organ Failure in Severe Sepsis
                                                                                                                                                                                                                                        • Mechanism of DIC in Organ Failure
                                                                                                                                                                                                                                        • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                                                                                        • Slide Number 47
                                                                                                                                                                                                                                        • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                                                                                        • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                                                                                        • Mechanism of DIC
                                                                                                                                                                                                                                        • Pathophysiology of DIC
                                                                                                                                                                                                                                        • Pathophysiology of DIC - Mechanism
                                                                                                                                                                                                                                        • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                                                                                        • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                                                                                        • Pathophysiology of Overt DIC
                                                                                                                                                                                                                                        • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                                                                                        • Slide Number 57
                                                                                                                                                                                                                                        • Slide Number 58
                                                                                                                                                                                                                                        • Slide Number 59
                                                                                                                                                                                                                                        • Slide Number 60
                                                                                                                                                                                                                                        • Slide Number 61
                                                                                                                                                                                                                                        • BREAK
                                                                                                                                                                                                                                        • Diagnostic and Management Approach for DIC
                                                                                                                                                                                                                                        • Diagnosis of DIC
                                                                                                                                                                                                                                        • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                                                                                        • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                                                                                        • Slide Number 67
                                                                                                                                                                                                                                        • Slide Number 68
                                                                                                                                                                                                                                        • British Journal of Haematology Overt DIC Score
                                                                                                                                                                                                                                        • Slide Number 70
                                                                                                                                                                                                                                        • Slide Number 71
                                                                                                                                                                                                                                        • Slide Number 72
                                                                                                                                                                                                                                        • Slide Number 73
                                                                                                                                                                                                                                        • DIC Management Goals
                                                                                                                                                                                                                                        • DIC Management and Treatment
                                                                                                                                                                                                                                        • DIC Management Strategies
                                                                                                                                                                                                                                        • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                                                                                        • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                                                                                        • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                                                                                        • D-dimer FDPs and DIC
                                                                                                                                                                                                                                        • D-Dimer and FDPs in DIC
                                                                                                                                                                                                                                        • Follow Up of DIC State of Disease
                                                                                                                                                                                                                                        • FMD-Dimer in DIC Major Differences
                                                                                                                                                                                                                                        • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                                                                                        • Slide Number 85
                                                                                                                                                                                                                                        • Slide Number 86
                                                                                                                                                                                                                                        • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                                                                                        • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                        • Slide Number 94
                                                                                                                                                                                                                                        • Slide Number 95
                                                                                                                                                                                                                                        • Slide Number 96
                                                                                                                                                                                                                                        • Slide Number 97
                                                                                                                                                                                                                                        • Slide Number 98
                                                                                                                                                                                                                                        • Slide Number 99
                                                                                                                                                                                                                                        • DIC Case Studies
                                                                                                                                                                                                                                        • Case Study 1 - Presentation
                                                                                                                                                                                                                                        • Case Study 1 ndash Lab Results
                                                                                                                                                                                                                                        • Case Study 1 ndash Microscopy
                                                                                                                                                                                                                                        • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                                                                                        • Slide Number 105
                                                                                                                                                                                                                                        • Slide Number 106
                                                                                                                                                                                                                                        • Slide Number 107
                                                                                                                                                                                                                                        • Slide Number 108
                                                                                                                                                                                                                                        • Slide Number 109
                                                                                                                                                                                                                                        • Slide Number 110
                                                                                                                                                                                                                                        • Slide Number 111
                                                                                                                                                                                                                                        • Slide Number 112
                                                                                                                                                                                                                                        • Slide Number 113
                                                                                                                                                                                                                                        • Slide Number 114
                                                                                                                                                                                                                                        • Slide Number 115
                                                                                                                                                                                                                                        • Slide Number 116
                                                                                                                                                                                                                                        • Slide Number 117
                                                                                                                                                                                                                                        • Slide Number 118
                                                                                                                                                                                                                                        • Slide Number 119
                                                                                                                                                                                                                                        • Slide Number 120
                                                                                                                                                                                                                                        • Slide Number 121
                                                                                                                                                                                                                                        • Slide Number 122
                                                                                                                                                                                                                                        • Slide Number 123
                                                                                                                                                                                                                                        • Slide Number 124
                                                                                                                                                                                                                                        • Slide Number 125
                                                                                                                                                                                                                                        • DIC Take Home Messages
                                                                                                                                                                                                                                        • Slide Number 127
                                                                                                                                                                                                                                        • Slide Number 128

                                                                                                                                                                                                                                          29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography

                                                                                                                                                                                                                                          Case Study 6 ndash Presentation

                                                                                                                                                                                                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                                          Case Study 6 ndash Lab Results

                                                                                                                                                                                                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                                          TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                                                                                                          PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                                                                                                          INR 658 1 ndash 125

                                                                                                                                                                                                                                          APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                                                                                                          D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                                                                                                          Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                                                                                                          Albumin 28 gdL NR

                                                                                                                                                                                                                                          Hb 58 gdL NR

                                                                                                                                                                                                                                          LDH 1196 UL NR

                                                                                                                                                                                                                                          SGPT 144 IU NR

                                                                                                                                                                                                                                          SGOT 88 IU NR

                                                                                                                                                                                                                                          Bilirubin 32 mgdL NR

                                                                                                                                                                                                                                          DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                                                                                                          day postop

                                                                                                                                                                                                                                          Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                                                                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                                          HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                                                                                                          Case Study 6 ndash Discussion

                                                                                                                                                                                                                                          Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                                          44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                                                                                                          Case Study 7 ndash Presentation

                                                                                                                                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                          On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                                                                                                          Case Study 7 ndash Presentation

                                                                                                                                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                          Case Study 7 ndash Lab Results vs Time

                                                                                                                                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                          Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                                                                                                          Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                          On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                                                                                          Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                          DIC Take Home Messages

                                                                                                                                                                                                                                          Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                                                                                          Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                                                                                          DIC

                                                                                                                                                                                                                                          Thank you Questions

                                                                                                                                                                                                                                          • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                                                                                          • Learning Objectives
                                                                                                                                                                                                                                          • Slide Number 3
                                                                                                                                                                                                                                          • Slide Number 4
                                                                                                                                                                                                                                          • Slide Number 5
                                                                                                                                                                                                                                          • Slide Number 6
                                                                                                                                                                                                                                          • Slide Number 7
                                                                                                                                                                                                                                          • Slide Number 8
                                                                                                                                                                                                                                          • Wound Sealing
                                                                                                                                                                                                                                          • The Three Steps of Hemostasis
                                                                                                                                                                                                                                          • Vessel Wall
                                                                                                                                                                                                                                          • Slide Number 12
                                                                                                                                                                                                                                          • Slide Number 13
                                                                                                                                                                                                                                          • Platelet Structure UnactivatedActivated
                                                                                                                                                                                                                                          • Primary Hemostasis
                                                                                                                                                                                                                                          • Primary Hemostasis Assays
                                                                                                                                                                                                                                          • Slide Number 17
                                                                                                                                                                                                                                          • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                                                                                          • Slide Number 19
                                                                                                                                                                                                                                          • Coagulation factors
                                                                                                                                                                                                                                          • Coagulation Assay Mechanisms
                                                                                                                                                                                                                                          • Slide Number 22
                                                                                                                                                                                                                                          • Fibrin Formation
                                                                                                                                                                                                                                          • Slide Number 24
                                                                                                                                                                                                                                          • Fibrinolysis Overview
                                                                                                                                                                                                                                          • Fibrinolysis Overview
                                                                                                                                                                                                                                          • Slide Number 27
                                                                                                                                                                                                                                          • Fibrinolysis Releases D-dimers
                                                                                                                                                                                                                                          • Basic Pathophysiology of DIC
                                                                                                                                                                                                                                          • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                                                                                          • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                                                                                          • Clinical Conditions Associated With DIC
                                                                                                                                                                                                                                          • Frequency of DIC in Selected Disease States
                                                                                                                                                                                                                                          • Underlying Diseases in DIC Patients
                                                                                                                                                                                                                                          • Slide Number 36
                                                                                                                                                                                                                                          • Slide Number 37
                                                                                                                                                                                                                                          • Slide Number 38
                                                                                                                                                                                                                                          • Slide Number 39
                                                                                                                                                                                                                                          • Pathophysiology of DIC
                                                                                                                                                                                                                                          • Pathogenesis of DIC in Sepsis
                                                                                                                                                                                                                                          • Host Response in Severe Sepsis
                                                                                                                                                                                                                                          • Organ Failure in Severe Sepsis
                                                                                                                                                                                                                                          • Mechanism of DIC in Organ Failure
                                                                                                                                                                                                                                          • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                                                                                          • Slide Number 47
                                                                                                                                                                                                                                          • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                                                                                          • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                                                                                          • Mechanism of DIC
                                                                                                                                                                                                                                          • Pathophysiology of DIC
                                                                                                                                                                                                                                          • Pathophysiology of DIC - Mechanism
                                                                                                                                                                                                                                          • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                                                                                          • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                                                                                          • Pathophysiology of Overt DIC
                                                                                                                                                                                                                                          • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                                                                                          • Slide Number 57
                                                                                                                                                                                                                                          • Slide Number 58
                                                                                                                                                                                                                                          • Slide Number 59
                                                                                                                                                                                                                                          • Slide Number 60
                                                                                                                                                                                                                                          • Slide Number 61
                                                                                                                                                                                                                                          • BREAK
                                                                                                                                                                                                                                          • Diagnostic and Management Approach for DIC
                                                                                                                                                                                                                                          • Diagnosis of DIC
                                                                                                                                                                                                                                          • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                                                                                          • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                                                                                          • Slide Number 67
                                                                                                                                                                                                                                          • Slide Number 68
                                                                                                                                                                                                                                          • British Journal of Haematology Overt DIC Score
                                                                                                                                                                                                                                          • Slide Number 70
                                                                                                                                                                                                                                          • Slide Number 71
                                                                                                                                                                                                                                          • Slide Number 72
                                                                                                                                                                                                                                          • Slide Number 73
                                                                                                                                                                                                                                          • DIC Management Goals
                                                                                                                                                                                                                                          • DIC Management and Treatment
                                                                                                                                                                                                                                          • DIC Management Strategies
                                                                                                                                                                                                                                          • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                                                                                          • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                                                                                          • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                                                                                          • D-dimer FDPs and DIC
                                                                                                                                                                                                                                          • D-Dimer and FDPs in DIC
                                                                                                                                                                                                                                          • Follow Up of DIC State of Disease
                                                                                                                                                                                                                                          • FMD-Dimer in DIC Major Differences
                                                                                                                                                                                                                                          • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                                                                                          • Slide Number 85
                                                                                                                                                                                                                                          • Slide Number 86
                                                                                                                                                                                                                                          • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                                                                                          • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                          • Slide Number 94
                                                                                                                                                                                                                                          • Slide Number 95
                                                                                                                                                                                                                                          • Slide Number 96
                                                                                                                                                                                                                                          • Slide Number 97
                                                                                                                                                                                                                                          • Slide Number 98
                                                                                                                                                                                                                                          • Slide Number 99
                                                                                                                                                                                                                                          • DIC Case Studies
                                                                                                                                                                                                                                          • Case Study 1 - Presentation
                                                                                                                                                                                                                                          • Case Study 1 ndash Lab Results
                                                                                                                                                                                                                                          • Case Study 1 ndash Microscopy
                                                                                                                                                                                                                                          • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                                                                                          • Slide Number 105
                                                                                                                                                                                                                                          • Slide Number 106
                                                                                                                                                                                                                                          • Slide Number 107
                                                                                                                                                                                                                                          • Slide Number 108
                                                                                                                                                                                                                                          • Slide Number 109
                                                                                                                                                                                                                                          • Slide Number 110
                                                                                                                                                                                                                                          • Slide Number 111
                                                                                                                                                                                                                                          • Slide Number 112
                                                                                                                                                                                                                                          • Slide Number 113
                                                                                                                                                                                                                                          • Slide Number 114
                                                                                                                                                                                                                                          • Slide Number 115
                                                                                                                                                                                                                                          • Slide Number 116
                                                                                                                                                                                                                                          • Slide Number 117
                                                                                                                                                                                                                                          • Slide Number 118
                                                                                                                                                                                                                                          • Slide Number 119
                                                                                                                                                                                                                                          • Slide Number 120
                                                                                                                                                                                                                                          • Slide Number 121
                                                                                                                                                                                                                                          • Slide Number 122
                                                                                                                                                                                                                                          • Slide Number 123
                                                                                                                                                                                                                                          • Slide Number 124
                                                                                                                                                                                                                                          • Slide Number 125
                                                                                                                                                                                                                                          • DIC Take Home Messages
                                                                                                                                                                                                                                          • Slide Number 127
                                                                                                                                                                                                                                          • Slide Number 128

                                                                                                                                                                                                                                            Case Study 6 ndash Lab Results

                                                                                                                                                                                                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                                            TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L

                                                                                                                                                                                                                                            PT 63 sec gt control 113 ndash 146 sec

                                                                                                                                                                                                                                            INR 658 1 ndash 125

                                                                                                                                                                                                                                            APTT 80 sec gt control 25 ndash 34 sec

                                                                                                                                                                                                                                            D-dimer gt200 microgmL DDU 02 microgmL DDU

                                                                                                                                                                                                                                            Urine exam Proteinuria and hematuria 150-400 mgdl

                                                                                                                                                                                                                                            Albumin 28 gdL NR

                                                                                                                                                                                                                                            Hb 58 gdL NR

                                                                                                                                                                                                                                            LDH 1196 UL NR

                                                                                                                                                                                                                                            SGPT 144 IU NR

                                                                                                                                                                                                                                            SGOT 88 IU NR

                                                                                                                                                                                                                                            Bilirubin 32 mgdL NR

                                                                                                                                                                                                                                            DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                                                                                                            day postop

                                                                                                                                                                                                                                            Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                                                                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                                            HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                                                                                                            Case Study 6 ndash Discussion

                                                                                                                                                                                                                                            Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                                            44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                                                                                                            Case Study 7 ndash Presentation

                                                                                                                                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                            On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                                                                                                            Case Study 7 ndash Presentation

                                                                                                                                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                            Case Study 7 ndash Lab Results vs Time

                                                                                                                                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                            Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                                                                                                            Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                            On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                                                                                            Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                                                            Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                            DIC Take Home Messages

                                                                                                                                                                                                                                            Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                                                                                            Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                                                                                            DIC

                                                                                                                                                                                                                                            Thank you Questions

                                                                                                                                                                                                                                            • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                                                                                            • Learning Objectives
                                                                                                                                                                                                                                            • Slide Number 3
                                                                                                                                                                                                                                            • Slide Number 4
                                                                                                                                                                                                                                            • Slide Number 5
                                                                                                                                                                                                                                            • Slide Number 6
                                                                                                                                                                                                                                            • Slide Number 7
                                                                                                                                                                                                                                            • Slide Number 8
                                                                                                                                                                                                                                            • Wound Sealing
                                                                                                                                                                                                                                            • The Three Steps of Hemostasis
                                                                                                                                                                                                                                            • Vessel Wall
                                                                                                                                                                                                                                            • Slide Number 12
                                                                                                                                                                                                                                            • Slide Number 13
                                                                                                                                                                                                                                            • Platelet Structure UnactivatedActivated
                                                                                                                                                                                                                                            • Primary Hemostasis
                                                                                                                                                                                                                                            • Primary Hemostasis Assays
                                                                                                                                                                                                                                            • Slide Number 17
                                                                                                                                                                                                                                            • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                                                                                            • Slide Number 19
                                                                                                                                                                                                                                            • Coagulation factors
                                                                                                                                                                                                                                            • Coagulation Assay Mechanisms
                                                                                                                                                                                                                                            • Slide Number 22
                                                                                                                                                                                                                                            • Fibrin Formation
                                                                                                                                                                                                                                            • Slide Number 24
                                                                                                                                                                                                                                            • Fibrinolysis Overview
                                                                                                                                                                                                                                            • Fibrinolysis Overview
                                                                                                                                                                                                                                            • Slide Number 27
                                                                                                                                                                                                                                            • Fibrinolysis Releases D-dimers
                                                                                                                                                                                                                                            • Basic Pathophysiology of DIC
                                                                                                                                                                                                                                            • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                                                                                            • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                                                                                            • Clinical Conditions Associated With DIC
                                                                                                                                                                                                                                            • Frequency of DIC in Selected Disease States
                                                                                                                                                                                                                                            • Underlying Diseases in DIC Patients
                                                                                                                                                                                                                                            • Slide Number 36
                                                                                                                                                                                                                                            • Slide Number 37
                                                                                                                                                                                                                                            • Slide Number 38
                                                                                                                                                                                                                                            • Slide Number 39
                                                                                                                                                                                                                                            • Pathophysiology of DIC
                                                                                                                                                                                                                                            • Pathogenesis of DIC in Sepsis
                                                                                                                                                                                                                                            • Host Response in Severe Sepsis
                                                                                                                                                                                                                                            • Organ Failure in Severe Sepsis
                                                                                                                                                                                                                                            • Mechanism of DIC in Organ Failure
                                                                                                                                                                                                                                            • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                                                                                            • Slide Number 47
                                                                                                                                                                                                                                            • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                                                                                            • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                                                                                            • Mechanism of DIC
                                                                                                                                                                                                                                            • Pathophysiology of DIC
                                                                                                                                                                                                                                            • Pathophysiology of DIC - Mechanism
                                                                                                                                                                                                                                            • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                                                                                            • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                                                                                            • Pathophysiology of Overt DIC
                                                                                                                                                                                                                                            • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                                                                                            • Slide Number 57
                                                                                                                                                                                                                                            • Slide Number 58
                                                                                                                                                                                                                                            • Slide Number 59
                                                                                                                                                                                                                                            • Slide Number 60
                                                                                                                                                                                                                                            • Slide Number 61
                                                                                                                                                                                                                                            • BREAK
                                                                                                                                                                                                                                            • Diagnostic and Management Approach for DIC
                                                                                                                                                                                                                                            • Diagnosis of DIC
                                                                                                                                                                                                                                            • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                                                                                            • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                                                                                            • Slide Number 67
                                                                                                                                                                                                                                            • Slide Number 68
                                                                                                                                                                                                                                            • British Journal of Haematology Overt DIC Score
                                                                                                                                                                                                                                            • Slide Number 70
                                                                                                                                                                                                                                            • Slide Number 71
                                                                                                                                                                                                                                            • Slide Number 72
                                                                                                                                                                                                                                            • Slide Number 73
                                                                                                                                                                                                                                            • DIC Management Goals
                                                                                                                                                                                                                                            • DIC Management and Treatment
                                                                                                                                                                                                                                            • DIC Management Strategies
                                                                                                                                                                                                                                            • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                                                                                            • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                                                                                            • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                                                                                            • D-dimer FDPs and DIC
                                                                                                                                                                                                                                            • D-Dimer and FDPs in DIC
                                                                                                                                                                                                                                            • Follow Up of DIC State of Disease
                                                                                                                                                                                                                                            • FMD-Dimer in DIC Major Differences
                                                                                                                                                                                                                                            • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                                                                                            • Slide Number 85
                                                                                                                                                                                                                                            • Slide Number 86
                                                                                                                                                                                                                                            • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                                                                                            • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                            • Slide Number 94
                                                                                                                                                                                                                                            • Slide Number 95
                                                                                                                                                                                                                                            • Slide Number 96
                                                                                                                                                                                                                                            • Slide Number 97
                                                                                                                                                                                                                                            • Slide Number 98
                                                                                                                                                                                                                                            • Slide Number 99
                                                                                                                                                                                                                                            • DIC Case Studies
                                                                                                                                                                                                                                            • Case Study 1 - Presentation
                                                                                                                                                                                                                                            • Case Study 1 ndash Lab Results
                                                                                                                                                                                                                                            • Case Study 1 ndash Microscopy
                                                                                                                                                                                                                                            • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                                                                                            • Slide Number 105
                                                                                                                                                                                                                                            • Slide Number 106
                                                                                                                                                                                                                                            • Slide Number 107
                                                                                                                                                                                                                                            • Slide Number 108
                                                                                                                                                                                                                                            • Slide Number 109
                                                                                                                                                                                                                                            • Slide Number 110
                                                                                                                                                                                                                                            • Slide Number 111
                                                                                                                                                                                                                                            • Slide Number 112
                                                                                                                                                                                                                                            • Slide Number 113
                                                                                                                                                                                                                                            • Slide Number 114
                                                                                                                                                                                                                                            • Slide Number 115
                                                                                                                                                                                                                                            • Slide Number 116
                                                                                                                                                                                                                                            • Slide Number 117
                                                                                                                                                                                                                                            • Slide Number 118
                                                                                                                                                                                                                                            • Slide Number 119
                                                                                                                                                                                                                                            • Slide Number 120
                                                                                                                                                                                                                                            • Slide Number 121
                                                                                                                                                                                                                                            • Slide Number 122
                                                                                                                                                                                                                                            • Slide Number 123
                                                                                                                                                                                                                                            • Slide Number 124
                                                                                                                                                                                                                                            • Slide Number 125
                                                                                                                                                                                                                                            • DIC Take Home Messages
                                                                                                                                                                                                                                            • Slide Number 127
                                                                                                                                                                                                                                            • Slide Number 128

                                                                                                                                                                                                                                              DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th

                                                                                                                                                                                                                                              day postop

                                                                                                                                                                                                                                              Case Study 6 ndash Diagnosis and Treatment

                                                                                                                                                                                                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                                              HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                                                                                                              Case Study 6 ndash Discussion

                                                                                                                                                                                                                                              Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                                              44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                                                                                                              Case Study 7 ndash Presentation

                                                                                                                                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                              On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                                                                                                              Case Study 7 ndash Presentation

                                                                                                                                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                              Case Study 7 ndash Lab Results vs Time

                                                                                                                                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                              Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                                                                                                              Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                              On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                                                                                              Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                                                              Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                              DIC Take Home Messages

                                                                                                                                                                                                                                              Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                                                                                              Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                                                                                              DIC

                                                                                                                                                                                                                                              Thank you Questions

                                                                                                                                                                                                                                              • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                                                                                              • Learning Objectives
                                                                                                                                                                                                                                              • Slide Number 3
                                                                                                                                                                                                                                              • Slide Number 4
                                                                                                                                                                                                                                              • Slide Number 5
                                                                                                                                                                                                                                              • Slide Number 6
                                                                                                                                                                                                                                              • Slide Number 7
                                                                                                                                                                                                                                              • Slide Number 8
                                                                                                                                                                                                                                              • Wound Sealing
                                                                                                                                                                                                                                              • The Three Steps of Hemostasis
                                                                                                                                                                                                                                              • Vessel Wall
                                                                                                                                                                                                                                              • Slide Number 12
                                                                                                                                                                                                                                              • Slide Number 13
                                                                                                                                                                                                                                              • Platelet Structure UnactivatedActivated
                                                                                                                                                                                                                                              • Primary Hemostasis
                                                                                                                                                                                                                                              • Primary Hemostasis Assays
                                                                                                                                                                                                                                              • Slide Number 17
                                                                                                                                                                                                                                              • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                                                                                              • Slide Number 19
                                                                                                                                                                                                                                              • Coagulation factors
                                                                                                                                                                                                                                              • Coagulation Assay Mechanisms
                                                                                                                                                                                                                                              • Slide Number 22
                                                                                                                                                                                                                                              • Fibrin Formation
                                                                                                                                                                                                                                              • Slide Number 24
                                                                                                                                                                                                                                              • Fibrinolysis Overview
                                                                                                                                                                                                                                              • Fibrinolysis Overview
                                                                                                                                                                                                                                              • Slide Number 27
                                                                                                                                                                                                                                              • Fibrinolysis Releases D-dimers
                                                                                                                                                                                                                                              • Basic Pathophysiology of DIC
                                                                                                                                                                                                                                              • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                                                                                              • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                                                                                              • Clinical Conditions Associated With DIC
                                                                                                                                                                                                                                              • Frequency of DIC in Selected Disease States
                                                                                                                                                                                                                                              • Underlying Diseases in DIC Patients
                                                                                                                                                                                                                                              • Slide Number 36
                                                                                                                                                                                                                                              • Slide Number 37
                                                                                                                                                                                                                                              • Slide Number 38
                                                                                                                                                                                                                                              • Slide Number 39
                                                                                                                                                                                                                                              • Pathophysiology of DIC
                                                                                                                                                                                                                                              • Pathogenesis of DIC in Sepsis
                                                                                                                                                                                                                                              • Host Response in Severe Sepsis
                                                                                                                                                                                                                                              • Organ Failure in Severe Sepsis
                                                                                                                                                                                                                                              • Mechanism of DIC in Organ Failure
                                                                                                                                                                                                                                              • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                                                                                              • Slide Number 47
                                                                                                                                                                                                                                              • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                                                                                              • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                                                                                              • Mechanism of DIC
                                                                                                                                                                                                                                              • Pathophysiology of DIC
                                                                                                                                                                                                                                              • Pathophysiology of DIC - Mechanism
                                                                                                                                                                                                                                              • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                                                                                              • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                                                                                              • Pathophysiology of Overt DIC
                                                                                                                                                                                                                                              • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                                                                                              • Slide Number 57
                                                                                                                                                                                                                                              • Slide Number 58
                                                                                                                                                                                                                                              • Slide Number 59
                                                                                                                                                                                                                                              • Slide Number 60
                                                                                                                                                                                                                                              • Slide Number 61
                                                                                                                                                                                                                                              • BREAK
                                                                                                                                                                                                                                              • Diagnostic and Management Approach for DIC
                                                                                                                                                                                                                                              • Diagnosis of DIC
                                                                                                                                                                                                                                              • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                                                                                              • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                                                                                              • Slide Number 67
                                                                                                                                                                                                                                              • Slide Number 68
                                                                                                                                                                                                                                              • British Journal of Haematology Overt DIC Score
                                                                                                                                                                                                                                              • Slide Number 70
                                                                                                                                                                                                                                              • Slide Number 71
                                                                                                                                                                                                                                              • Slide Number 72
                                                                                                                                                                                                                                              • Slide Number 73
                                                                                                                                                                                                                                              • DIC Management Goals
                                                                                                                                                                                                                                              • DIC Management and Treatment
                                                                                                                                                                                                                                              • DIC Management Strategies
                                                                                                                                                                                                                                              • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                                                                                              • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                                                                                              • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                                                                                              • D-dimer FDPs and DIC
                                                                                                                                                                                                                                              • D-Dimer and FDPs in DIC
                                                                                                                                                                                                                                              • Follow Up of DIC State of Disease
                                                                                                                                                                                                                                              • FMD-Dimer in DIC Major Differences
                                                                                                                                                                                                                                              • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                                                                                              • Slide Number 85
                                                                                                                                                                                                                                              • Slide Number 86
                                                                                                                                                                                                                                              • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                                                                                              • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                              • Slide Number 94
                                                                                                                                                                                                                                              • Slide Number 95
                                                                                                                                                                                                                                              • Slide Number 96
                                                                                                                                                                                                                                              • Slide Number 97
                                                                                                                                                                                                                                              • Slide Number 98
                                                                                                                                                                                                                                              • Slide Number 99
                                                                                                                                                                                                                                              • DIC Case Studies
                                                                                                                                                                                                                                              • Case Study 1 - Presentation
                                                                                                                                                                                                                                              • Case Study 1 ndash Lab Results
                                                                                                                                                                                                                                              • Case Study 1 ndash Microscopy
                                                                                                                                                                                                                                              • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                                                                                              • Slide Number 105
                                                                                                                                                                                                                                              • Slide Number 106
                                                                                                                                                                                                                                              • Slide Number 107
                                                                                                                                                                                                                                              • Slide Number 108
                                                                                                                                                                                                                                              • Slide Number 109
                                                                                                                                                                                                                                              • Slide Number 110
                                                                                                                                                                                                                                              • Slide Number 111
                                                                                                                                                                                                                                              • Slide Number 112
                                                                                                                                                                                                                                              • Slide Number 113
                                                                                                                                                                                                                                              • Slide Number 114
                                                                                                                                                                                                                                              • Slide Number 115
                                                                                                                                                                                                                                              • Slide Number 116
                                                                                                                                                                                                                                              • Slide Number 117
                                                                                                                                                                                                                                              • Slide Number 118
                                                                                                                                                                                                                                              • Slide Number 119
                                                                                                                                                                                                                                              • Slide Number 120
                                                                                                                                                                                                                                              • Slide Number 121
                                                                                                                                                                                                                                              • Slide Number 122
                                                                                                                                                                                                                                              • Slide Number 123
                                                                                                                                                                                                                                              • Slide Number 124
                                                                                                                                                                                                                                              • Slide Number 125
                                                                                                                                                                                                                                              • DIC Take Home Messages
                                                                                                                                                                                                                                              • Slide Number 127
                                                                                                                                                                                                                                              • Slide Number 128

                                                                                                                                                                                                                                                HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure

                                                                                                                                                                                                                                                Case Study 6 ndash Discussion

                                                                                                                                                                                                                                                Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027

                                                                                                                                                                                                                                                44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                                                                                                                Case Study 7 ndash Presentation

                                                                                                                                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                                On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                                                                                                                Case Study 7 ndash Presentation

                                                                                                                                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                                Case Study 7 ndash Lab Results vs Time

                                                                                                                                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                                Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                                                                                                                Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                                On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                                                                                                Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                                                                Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                                DIC Take Home Messages

                                                                                                                                                                                                                                                Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                                                                                                Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                                                                                                DIC

                                                                                                                                                                                                                                                Thank you Questions

                                                                                                                                                                                                                                                • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                                                                                                • Learning Objectives
                                                                                                                                                                                                                                                • Slide Number 3
                                                                                                                                                                                                                                                • Slide Number 4
                                                                                                                                                                                                                                                • Slide Number 5
                                                                                                                                                                                                                                                • Slide Number 6
                                                                                                                                                                                                                                                • Slide Number 7
                                                                                                                                                                                                                                                • Slide Number 8
                                                                                                                                                                                                                                                • Wound Sealing
                                                                                                                                                                                                                                                • The Three Steps of Hemostasis
                                                                                                                                                                                                                                                • Vessel Wall
                                                                                                                                                                                                                                                • Slide Number 12
                                                                                                                                                                                                                                                • Slide Number 13
                                                                                                                                                                                                                                                • Platelet Structure UnactivatedActivated
                                                                                                                                                                                                                                                • Primary Hemostasis
                                                                                                                                                                                                                                                • Primary Hemostasis Assays
                                                                                                                                                                                                                                                • Slide Number 17
                                                                                                                                                                                                                                                • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                                                                                                • Slide Number 19
                                                                                                                                                                                                                                                • Coagulation factors
                                                                                                                                                                                                                                                • Coagulation Assay Mechanisms
                                                                                                                                                                                                                                                • Slide Number 22
                                                                                                                                                                                                                                                • Fibrin Formation
                                                                                                                                                                                                                                                • Slide Number 24
                                                                                                                                                                                                                                                • Fibrinolysis Overview
                                                                                                                                                                                                                                                • Fibrinolysis Overview
                                                                                                                                                                                                                                                • Slide Number 27
                                                                                                                                                                                                                                                • Fibrinolysis Releases D-dimers
                                                                                                                                                                                                                                                • Basic Pathophysiology of DIC
                                                                                                                                                                                                                                                • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                                                                                                • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                                                                                                • Clinical Conditions Associated With DIC
                                                                                                                                                                                                                                                • Frequency of DIC in Selected Disease States
                                                                                                                                                                                                                                                • Underlying Diseases in DIC Patients
                                                                                                                                                                                                                                                • Slide Number 36
                                                                                                                                                                                                                                                • Slide Number 37
                                                                                                                                                                                                                                                • Slide Number 38
                                                                                                                                                                                                                                                • Slide Number 39
                                                                                                                                                                                                                                                • Pathophysiology of DIC
                                                                                                                                                                                                                                                • Pathogenesis of DIC in Sepsis
                                                                                                                                                                                                                                                • Host Response in Severe Sepsis
                                                                                                                                                                                                                                                • Organ Failure in Severe Sepsis
                                                                                                                                                                                                                                                • Mechanism of DIC in Organ Failure
                                                                                                                                                                                                                                                • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                                                                                                • Slide Number 47
                                                                                                                                                                                                                                                • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                                                                                                • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                                                                                                • Mechanism of DIC
                                                                                                                                                                                                                                                • Pathophysiology of DIC
                                                                                                                                                                                                                                                • Pathophysiology of DIC - Mechanism
                                                                                                                                                                                                                                                • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                                                                                                • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                                                                                                • Pathophysiology of Overt DIC
                                                                                                                                                                                                                                                • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                                                                                                • Slide Number 57
                                                                                                                                                                                                                                                • Slide Number 58
                                                                                                                                                                                                                                                • Slide Number 59
                                                                                                                                                                                                                                                • Slide Number 60
                                                                                                                                                                                                                                                • Slide Number 61
                                                                                                                                                                                                                                                • BREAK
                                                                                                                                                                                                                                                • Diagnostic and Management Approach for DIC
                                                                                                                                                                                                                                                • Diagnosis of DIC
                                                                                                                                                                                                                                                • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                                                                                                • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                                                                                                • Slide Number 67
                                                                                                                                                                                                                                                • Slide Number 68
                                                                                                                                                                                                                                                • British Journal of Haematology Overt DIC Score
                                                                                                                                                                                                                                                • Slide Number 70
                                                                                                                                                                                                                                                • Slide Number 71
                                                                                                                                                                                                                                                • Slide Number 72
                                                                                                                                                                                                                                                • Slide Number 73
                                                                                                                                                                                                                                                • DIC Management Goals
                                                                                                                                                                                                                                                • DIC Management and Treatment
                                                                                                                                                                                                                                                • DIC Management Strategies
                                                                                                                                                                                                                                                • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                                                                                                • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                                                                                                • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                                                                                                • D-dimer FDPs and DIC
                                                                                                                                                                                                                                                • D-Dimer and FDPs in DIC
                                                                                                                                                                                                                                                • Follow Up of DIC State of Disease
                                                                                                                                                                                                                                                • FMD-Dimer in DIC Major Differences
                                                                                                                                                                                                                                                • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                                                                                                • Slide Number 85
                                                                                                                                                                                                                                                • Slide Number 86
                                                                                                                                                                                                                                                • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                                                                                                • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                • Slide Number 94
                                                                                                                                                                                                                                                • Slide Number 95
                                                                                                                                                                                                                                                • Slide Number 96
                                                                                                                                                                                                                                                • Slide Number 97
                                                                                                                                                                                                                                                • Slide Number 98
                                                                                                                                                                                                                                                • Slide Number 99
                                                                                                                                                                                                                                                • DIC Case Studies
                                                                                                                                                                                                                                                • Case Study 1 - Presentation
                                                                                                                                                                                                                                                • Case Study 1 ndash Lab Results
                                                                                                                                                                                                                                                • Case Study 1 ndash Microscopy
                                                                                                                                                                                                                                                • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                                                                                                • Slide Number 105
                                                                                                                                                                                                                                                • Slide Number 106
                                                                                                                                                                                                                                                • Slide Number 107
                                                                                                                                                                                                                                                • Slide Number 108
                                                                                                                                                                                                                                                • Slide Number 109
                                                                                                                                                                                                                                                • Slide Number 110
                                                                                                                                                                                                                                                • Slide Number 111
                                                                                                                                                                                                                                                • Slide Number 112
                                                                                                                                                                                                                                                • Slide Number 113
                                                                                                                                                                                                                                                • Slide Number 114
                                                                                                                                                                                                                                                • Slide Number 115
                                                                                                                                                                                                                                                • Slide Number 116
                                                                                                                                                                                                                                                • Slide Number 117
                                                                                                                                                                                                                                                • Slide Number 118
                                                                                                                                                                                                                                                • Slide Number 119
                                                                                                                                                                                                                                                • Slide Number 120
                                                                                                                                                                                                                                                • Slide Number 121
                                                                                                                                                                                                                                                • Slide Number 122
                                                                                                                                                                                                                                                • Slide Number 123
                                                                                                                                                                                                                                                • Slide Number 124
                                                                                                                                                                                                                                                • Slide Number 125
                                                                                                                                                                                                                                                • DIC Take Home Messages
                                                                                                                                                                                                                                                • Slide Number 127
                                                                                                                                                                                                                                                • Slide Number 128

                                                                                                                                                                                                                                                  44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF

                                                                                                                                                                                                                                                  Case Study 7 ndash Presentation

                                                                                                                                                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                                  On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                                                                                                                  Case Study 7 ndash Presentation

                                                                                                                                                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                                  Case Study 7 ndash Lab Results vs Time

                                                                                                                                                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                                  Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                                                                                                                  Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                                  On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                                                                                                  Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                                                                  Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                                  DIC Take Home Messages

                                                                                                                                                                                                                                                  Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                                                                                                  Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                                                                                                  DIC

                                                                                                                                                                                                                                                  Thank you Questions

                                                                                                                                                                                                                                                  • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                                                                                                  • Learning Objectives
                                                                                                                                                                                                                                                  • Slide Number 3
                                                                                                                                                                                                                                                  • Slide Number 4
                                                                                                                                                                                                                                                  • Slide Number 5
                                                                                                                                                                                                                                                  • Slide Number 6
                                                                                                                                                                                                                                                  • Slide Number 7
                                                                                                                                                                                                                                                  • Slide Number 8
                                                                                                                                                                                                                                                  • Wound Sealing
                                                                                                                                                                                                                                                  • The Three Steps of Hemostasis
                                                                                                                                                                                                                                                  • Vessel Wall
                                                                                                                                                                                                                                                  • Slide Number 12
                                                                                                                                                                                                                                                  • Slide Number 13
                                                                                                                                                                                                                                                  • Platelet Structure UnactivatedActivated
                                                                                                                                                                                                                                                  • Primary Hemostasis
                                                                                                                                                                                                                                                  • Primary Hemostasis Assays
                                                                                                                                                                                                                                                  • Slide Number 17
                                                                                                                                                                                                                                                  • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                                                                                                  • Slide Number 19
                                                                                                                                                                                                                                                  • Coagulation factors
                                                                                                                                                                                                                                                  • Coagulation Assay Mechanisms
                                                                                                                                                                                                                                                  • Slide Number 22
                                                                                                                                                                                                                                                  • Fibrin Formation
                                                                                                                                                                                                                                                  • Slide Number 24
                                                                                                                                                                                                                                                  • Fibrinolysis Overview
                                                                                                                                                                                                                                                  • Fibrinolysis Overview
                                                                                                                                                                                                                                                  • Slide Number 27
                                                                                                                                                                                                                                                  • Fibrinolysis Releases D-dimers
                                                                                                                                                                                                                                                  • Basic Pathophysiology of DIC
                                                                                                                                                                                                                                                  • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                                                                                                  • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                                                                                                  • Clinical Conditions Associated With DIC
                                                                                                                                                                                                                                                  • Frequency of DIC in Selected Disease States
                                                                                                                                                                                                                                                  • Underlying Diseases in DIC Patients
                                                                                                                                                                                                                                                  • Slide Number 36
                                                                                                                                                                                                                                                  • Slide Number 37
                                                                                                                                                                                                                                                  • Slide Number 38
                                                                                                                                                                                                                                                  • Slide Number 39
                                                                                                                                                                                                                                                  • Pathophysiology of DIC
                                                                                                                                                                                                                                                  • Pathogenesis of DIC in Sepsis
                                                                                                                                                                                                                                                  • Host Response in Severe Sepsis
                                                                                                                                                                                                                                                  • Organ Failure in Severe Sepsis
                                                                                                                                                                                                                                                  • Mechanism of DIC in Organ Failure
                                                                                                                                                                                                                                                  • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                                                                                                  • Slide Number 47
                                                                                                                                                                                                                                                  • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                                                                                                  • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                                                                                                  • Mechanism of DIC
                                                                                                                                                                                                                                                  • Pathophysiology of DIC
                                                                                                                                                                                                                                                  • Pathophysiology of DIC - Mechanism
                                                                                                                                                                                                                                                  • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                                                                                                  • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                                                                                                  • Pathophysiology of Overt DIC
                                                                                                                                                                                                                                                  • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                                                                                                  • Slide Number 57
                                                                                                                                                                                                                                                  • Slide Number 58
                                                                                                                                                                                                                                                  • Slide Number 59
                                                                                                                                                                                                                                                  • Slide Number 60
                                                                                                                                                                                                                                                  • Slide Number 61
                                                                                                                                                                                                                                                  • BREAK
                                                                                                                                                                                                                                                  • Diagnostic and Management Approach for DIC
                                                                                                                                                                                                                                                  • Diagnosis of DIC
                                                                                                                                                                                                                                                  • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                                                                                                  • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                                                                                                  • Slide Number 67
                                                                                                                                                                                                                                                  • Slide Number 68
                                                                                                                                                                                                                                                  • British Journal of Haematology Overt DIC Score
                                                                                                                                                                                                                                                  • Slide Number 70
                                                                                                                                                                                                                                                  • Slide Number 71
                                                                                                                                                                                                                                                  • Slide Number 72
                                                                                                                                                                                                                                                  • Slide Number 73
                                                                                                                                                                                                                                                  • DIC Management Goals
                                                                                                                                                                                                                                                  • DIC Management and Treatment
                                                                                                                                                                                                                                                  • DIC Management Strategies
                                                                                                                                                                                                                                                  • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                                                                                                  • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                                                                                                  • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                                                                                                  • D-dimer FDPs and DIC
                                                                                                                                                                                                                                                  • D-Dimer and FDPs in DIC
                                                                                                                                                                                                                                                  • Follow Up of DIC State of Disease
                                                                                                                                                                                                                                                  • FMD-Dimer in DIC Major Differences
                                                                                                                                                                                                                                                  • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                                                                                                  • Slide Number 85
                                                                                                                                                                                                                                                  • Slide Number 86
                                                                                                                                                                                                                                                  • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                                                                                                  • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                  • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                  • Slide Number 94
                                                                                                                                                                                                                                                  • Slide Number 95
                                                                                                                                                                                                                                                  • Slide Number 96
                                                                                                                                                                                                                                                  • Slide Number 97
                                                                                                                                                                                                                                                  • Slide Number 98
                                                                                                                                                                                                                                                  • Slide Number 99
                                                                                                                                                                                                                                                  • DIC Case Studies
                                                                                                                                                                                                                                                  • Case Study 1 - Presentation
                                                                                                                                                                                                                                                  • Case Study 1 ndash Lab Results
                                                                                                                                                                                                                                                  • Case Study 1 ndash Microscopy
                                                                                                                                                                                                                                                  • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                                                                                                  • Slide Number 105
                                                                                                                                                                                                                                                  • Slide Number 106
                                                                                                                                                                                                                                                  • Slide Number 107
                                                                                                                                                                                                                                                  • Slide Number 108
                                                                                                                                                                                                                                                  • Slide Number 109
                                                                                                                                                                                                                                                  • Slide Number 110
                                                                                                                                                                                                                                                  • Slide Number 111
                                                                                                                                                                                                                                                  • Slide Number 112
                                                                                                                                                                                                                                                  • Slide Number 113
                                                                                                                                                                                                                                                  • Slide Number 114
                                                                                                                                                                                                                                                  • Slide Number 115
                                                                                                                                                                                                                                                  • Slide Number 116
                                                                                                                                                                                                                                                  • Slide Number 117
                                                                                                                                                                                                                                                  • Slide Number 118
                                                                                                                                                                                                                                                  • Slide Number 119
                                                                                                                                                                                                                                                  • Slide Number 120
                                                                                                                                                                                                                                                  • Slide Number 121
                                                                                                                                                                                                                                                  • Slide Number 122
                                                                                                                                                                                                                                                  • Slide Number 123
                                                                                                                                                                                                                                                  • Slide Number 124
                                                                                                                                                                                                                                                  • Slide Number 125
                                                                                                                                                                                                                                                  • DIC Take Home Messages
                                                                                                                                                                                                                                                  • Slide Number 127
                                                                                                                                                                                                                                                  • Slide Number 128

                                                                                                                                                                                                                                                    On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25

                                                                                                                                                                                                                                                    Case Study 7 ndash Presentation

                                                                                                                                                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                                    Case Study 7 ndash Lab Results vs Time

                                                                                                                                                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                                    Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                                                                                                                    Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                                    On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                                                                                                    Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                                                                    Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                                    DIC Take Home Messages

                                                                                                                                                                                                                                                    Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                                                                                                    Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                                                                                                    DIC

                                                                                                                                                                                                                                                    Thank you Questions

                                                                                                                                                                                                                                                    • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                                                                                                    • Learning Objectives
                                                                                                                                                                                                                                                    • Slide Number 3
                                                                                                                                                                                                                                                    • Slide Number 4
                                                                                                                                                                                                                                                    • Slide Number 5
                                                                                                                                                                                                                                                    • Slide Number 6
                                                                                                                                                                                                                                                    • Slide Number 7
                                                                                                                                                                                                                                                    • Slide Number 8
                                                                                                                                                                                                                                                    • Wound Sealing
                                                                                                                                                                                                                                                    • The Three Steps of Hemostasis
                                                                                                                                                                                                                                                    • Vessel Wall
                                                                                                                                                                                                                                                    • Slide Number 12
                                                                                                                                                                                                                                                    • Slide Number 13
                                                                                                                                                                                                                                                    • Platelet Structure UnactivatedActivated
                                                                                                                                                                                                                                                    • Primary Hemostasis
                                                                                                                                                                                                                                                    • Primary Hemostasis Assays
                                                                                                                                                                                                                                                    • Slide Number 17
                                                                                                                                                                                                                                                    • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                                                                                                    • Slide Number 19
                                                                                                                                                                                                                                                    • Coagulation factors
                                                                                                                                                                                                                                                    • Coagulation Assay Mechanisms
                                                                                                                                                                                                                                                    • Slide Number 22
                                                                                                                                                                                                                                                    • Fibrin Formation
                                                                                                                                                                                                                                                    • Slide Number 24
                                                                                                                                                                                                                                                    • Fibrinolysis Overview
                                                                                                                                                                                                                                                    • Fibrinolysis Overview
                                                                                                                                                                                                                                                    • Slide Number 27
                                                                                                                                                                                                                                                    • Fibrinolysis Releases D-dimers
                                                                                                                                                                                                                                                    • Basic Pathophysiology of DIC
                                                                                                                                                                                                                                                    • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                                                                                                    • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                                                                                                    • Clinical Conditions Associated With DIC
                                                                                                                                                                                                                                                    • Frequency of DIC in Selected Disease States
                                                                                                                                                                                                                                                    • Underlying Diseases in DIC Patients
                                                                                                                                                                                                                                                    • Slide Number 36
                                                                                                                                                                                                                                                    • Slide Number 37
                                                                                                                                                                                                                                                    • Slide Number 38
                                                                                                                                                                                                                                                    • Slide Number 39
                                                                                                                                                                                                                                                    • Pathophysiology of DIC
                                                                                                                                                                                                                                                    • Pathogenesis of DIC in Sepsis
                                                                                                                                                                                                                                                    • Host Response in Severe Sepsis
                                                                                                                                                                                                                                                    • Organ Failure in Severe Sepsis
                                                                                                                                                                                                                                                    • Mechanism of DIC in Organ Failure
                                                                                                                                                                                                                                                    • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                                                                                                    • Slide Number 47
                                                                                                                                                                                                                                                    • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                                                                                                    • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                                                                                                    • Mechanism of DIC
                                                                                                                                                                                                                                                    • Pathophysiology of DIC
                                                                                                                                                                                                                                                    • Pathophysiology of DIC - Mechanism
                                                                                                                                                                                                                                                    • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                                                                                                    • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                                                                                                    • Pathophysiology of Overt DIC
                                                                                                                                                                                                                                                    • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                                                                                                    • Slide Number 57
                                                                                                                                                                                                                                                    • Slide Number 58
                                                                                                                                                                                                                                                    • Slide Number 59
                                                                                                                                                                                                                                                    • Slide Number 60
                                                                                                                                                                                                                                                    • Slide Number 61
                                                                                                                                                                                                                                                    • BREAK
                                                                                                                                                                                                                                                    • Diagnostic and Management Approach for DIC
                                                                                                                                                                                                                                                    • Diagnosis of DIC
                                                                                                                                                                                                                                                    • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                                                                                                    • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                                                                                                    • Slide Number 67
                                                                                                                                                                                                                                                    • Slide Number 68
                                                                                                                                                                                                                                                    • British Journal of Haematology Overt DIC Score
                                                                                                                                                                                                                                                    • Slide Number 70
                                                                                                                                                                                                                                                    • Slide Number 71
                                                                                                                                                                                                                                                    • Slide Number 72
                                                                                                                                                                                                                                                    • Slide Number 73
                                                                                                                                                                                                                                                    • DIC Management Goals
                                                                                                                                                                                                                                                    • DIC Management and Treatment
                                                                                                                                                                                                                                                    • DIC Management Strategies
                                                                                                                                                                                                                                                    • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                                                                                                    • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                                                                                                    • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                                                                                                    • D-dimer FDPs and DIC
                                                                                                                                                                                                                                                    • D-Dimer and FDPs in DIC
                                                                                                                                                                                                                                                    • Follow Up of DIC State of Disease
                                                                                                                                                                                                                                                    • FMD-Dimer in DIC Major Differences
                                                                                                                                                                                                                                                    • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                                                                                                    • Slide Number 85
                                                                                                                                                                                                                                                    • Slide Number 86
                                                                                                                                                                                                                                                    • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                                                                                                    • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                    • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                    • Slide Number 94
                                                                                                                                                                                                                                                    • Slide Number 95
                                                                                                                                                                                                                                                    • Slide Number 96
                                                                                                                                                                                                                                                    • Slide Number 97
                                                                                                                                                                                                                                                    • Slide Number 98
                                                                                                                                                                                                                                                    • Slide Number 99
                                                                                                                                                                                                                                                    • DIC Case Studies
                                                                                                                                                                                                                                                    • Case Study 1 - Presentation
                                                                                                                                                                                                                                                    • Case Study 1 ndash Lab Results
                                                                                                                                                                                                                                                    • Case Study 1 ndash Microscopy
                                                                                                                                                                                                                                                    • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                                                                                                    • Slide Number 105
                                                                                                                                                                                                                                                    • Slide Number 106
                                                                                                                                                                                                                                                    • Slide Number 107
                                                                                                                                                                                                                                                    • Slide Number 108
                                                                                                                                                                                                                                                    • Slide Number 109
                                                                                                                                                                                                                                                    • Slide Number 110
                                                                                                                                                                                                                                                    • Slide Number 111
                                                                                                                                                                                                                                                    • Slide Number 112
                                                                                                                                                                                                                                                    • Slide Number 113
                                                                                                                                                                                                                                                    • Slide Number 114
                                                                                                                                                                                                                                                    • Slide Number 115
                                                                                                                                                                                                                                                    • Slide Number 116
                                                                                                                                                                                                                                                    • Slide Number 117
                                                                                                                                                                                                                                                    • Slide Number 118
                                                                                                                                                                                                                                                    • Slide Number 119
                                                                                                                                                                                                                                                    • Slide Number 120
                                                                                                                                                                                                                                                    • Slide Number 121
                                                                                                                                                                                                                                                    • Slide Number 122
                                                                                                                                                                                                                                                    • Slide Number 123
                                                                                                                                                                                                                                                    • Slide Number 124
                                                                                                                                                                                                                                                    • Slide Number 125
                                                                                                                                                                                                                                                    • DIC Take Home Messages
                                                                                                                                                                                                                                                    • Slide Number 127
                                                                                                                                                                                                                                                    • Slide Number 128

                                                                                                                                                                                                                                                      Case Study 7 ndash Lab Results vs Time

                                                                                                                                                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                                      Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                                                                                                                      Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                                      On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                                                                                                      Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                                                                      Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                                      DIC Take Home Messages

                                                                                                                                                                                                                                                      Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                                                                                                      Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                                                                                                      DIC

                                                                                                                                                                                                                                                      Thank you Questions

                                                                                                                                                                                                                                                      • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                                                                                                      • Learning Objectives
                                                                                                                                                                                                                                                      • Slide Number 3
                                                                                                                                                                                                                                                      • Slide Number 4
                                                                                                                                                                                                                                                      • Slide Number 5
                                                                                                                                                                                                                                                      • Slide Number 6
                                                                                                                                                                                                                                                      • Slide Number 7
                                                                                                                                                                                                                                                      • Slide Number 8
                                                                                                                                                                                                                                                      • Wound Sealing
                                                                                                                                                                                                                                                      • The Three Steps of Hemostasis
                                                                                                                                                                                                                                                      • Vessel Wall
                                                                                                                                                                                                                                                      • Slide Number 12
                                                                                                                                                                                                                                                      • Slide Number 13
                                                                                                                                                                                                                                                      • Platelet Structure UnactivatedActivated
                                                                                                                                                                                                                                                      • Primary Hemostasis
                                                                                                                                                                                                                                                      • Primary Hemostasis Assays
                                                                                                                                                                                                                                                      • Slide Number 17
                                                                                                                                                                                                                                                      • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                                                                                                      • Slide Number 19
                                                                                                                                                                                                                                                      • Coagulation factors
                                                                                                                                                                                                                                                      • Coagulation Assay Mechanisms
                                                                                                                                                                                                                                                      • Slide Number 22
                                                                                                                                                                                                                                                      • Fibrin Formation
                                                                                                                                                                                                                                                      • Slide Number 24
                                                                                                                                                                                                                                                      • Fibrinolysis Overview
                                                                                                                                                                                                                                                      • Fibrinolysis Overview
                                                                                                                                                                                                                                                      • Slide Number 27
                                                                                                                                                                                                                                                      • Fibrinolysis Releases D-dimers
                                                                                                                                                                                                                                                      • Basic Pathophysiology of DIC
                                                                                                                                                                                                                                                      • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                                                                                                      • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                                                                                                      • Clinical Conditions Associated With DIC
                                                                                                                                                                                                                                                      • Frequency of DIC in Selected Disease States
                                                                                                                                                                                                                                                      • Underlying Diseases in DIC Patients
                                                                                                                                                                                                                                                      • Slide Number 36
                                                                                                                                                                                                                                                      • Slide Number 37
                                                                                                                                                                                                                                                      • Slide Number 38
                                                                                                                                                                                                                                                      • Slide Number 39
                                                                                                                                                                                                                                                      • Pathophysiology of DIC
                                                                                                                                                                                                                                                      • Pathogenesis of DIC in Sepsis
                                                                                                                                                                                                                                                      • Host Response in Severe Sepsis
                                                                                                                                                                                                                                                      • Organ Failure in Severe Sepsis
                                                                                                                                                                                                                                                      • Mechanism of DIC in Organ Failure
                                                                                                                                                                                                                                                      • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                                                                                                      • Slide Number 47
                                                                                                                                                                                                                                                      • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                                                                                                      • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                                                                                                      • Mechanism of DIC
                                                                                                                                                                                                                                                      • Pathophysiology of DIC
                                                                                                                                                                                                                                                      • Pathophysiology of DIC - Mechanism
                                                                                                                                                                                                                                                      • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                                                                                                      • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                                                                                                      • Pathophysiology of Overt DIC
                                                                                                                                                                                                                                                      • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                                                                                                      • Slide Number 57
                                                                                                                                                                                                                                                      • Slide Number 58
                                                                                                                                                                                                                                                      • Slide Number 59
                                                                                                                                                                                                                                                      • Slide Number 60
                                                                                                                                                                                                                                                      • Slide Number 61
                                                                                                                                                                                                                                                      • BREAK
                                                                                                                                                                                                                                                      • Diagnostic and Management Approach for DIC
                                                                                                                                                                                                                                                      • Diagnosis of DIC
                                                                                                                                                                                                                                                      • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                                                                                                      • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                                                                                                      • Slide Number 67
                                                                                                                                                                                                                                                      • Slide Number 68
                                                                                                                                                                                                                                                      • British Journal of Haematology Overt DIC Score
                                                                                                                                                                                                                                                      • Slide Number 70
                                                                                                                                                                                                                                                      • Slide Number 71
                                                                                                                                                                                                                                                      • Slide Number 72
                                                                                                                                                                                                                                                      • Slide Number 73
                                                                                                                                                                                                                                                      • DIC Management Goals
                                                                                                                                                                                                                                                      • DIC Management and Treatment
                                                                                                                                                                                                                                                      • DIC Management Strategies
                                                                                                                                                                                                                                                      • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                                                                                                      • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                                                                                                      • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                                                                                                      • D-dimer FDPs and DIC
                                                                                                                                                                                                                                                      • D-Dimer and FDPs in DIC
                                                                                                                                                                                                                                                      • Follow Up of DIC State of Disease
                                                                                                                                                                                                                                                      • FMD-Dimer in DIC Major Differences
                                                                                                                                                                                                                                                      • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                                                                                                      • Slide Number 85
                                                                                                                                                                                                                                                      • Slide Number 86
                                                                                                                                                                                                                                                      • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                                                                                                      • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                      • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                      • Slide Number 94
                                                                                                                                                                                                                                                      • Slide Number 95
                                                                                                                                                                                                                                                      • Slide Number 96
                                                                                                                                                                                                                                                      • Slide Number 97
                                                                                                                                                                                                                                                      • Slide Number 98
                                                                                                                                                                                                                                                      • Slide Number 99
                                                                                                                                                                                                                                                      • DIC Case Studies
                                                                                                                                                                                                                                                      • Case Study 1 - Presentation
                                                                                                                                                                                                                                                      • Case Study 1 ndash Lab Results
                                                                                                                                                                                                                                                      • Case Study 1 ndash Microscopy
                                                                                                                                                                                                                                                      • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                                                                                                      • Slide Number 105
                                                                                                                                                                                                                                                      • Slide Number 106
                                                                                                                                                                                                                                                      • Slide Number 107
                                                                                                                                                                                                                                                      • Slide Number 108
                                                                                                                                                                                                                                                      • Slide Number 109
                                                                                                                                                                                                                                                      • Slide Number 110
                                                                                                                                                                                                                                                      • Slide Number 111
                                                                                                                                                                                                                                                      • Slide Number 112
                                                                                                                                                                                                                                                      • Slide Number 113
                                                                                                                                                                                                                                                      • Slide Number 114
                                                                                                                                                                                                                                                      • Slide Number 115
                                                                                                                                                                                                                                                      • Slide Number 116
                                                                                                                                                                                                                                                      • Slide Number 117
                                                                                                                                                                                                                                                      • Slide Number 118
                                                                                                                                                                                                                                                      • Slide Number 119
                                                                                                                                                                                                                                                      • Slide Number 120
                                                                                                                                                                                                                                                      • Slide Number 121
                                                                                                                                                                                                                                                      • Slide Number 122
                                                                                                                                                                                                                                                      • Slide Number 123
                                                                                                                                                                                                                                                      • Slide Number 124
                                                                                                                                                                                                                                                      • Slide Number 125
                                                                                                                                                                                                                                                      • DIC Take Home Messages
                                                                                                                                                                                                                                                      • Slide Number 127
                                                                                                                                                                                                                                                      • Slide Number 128

                                                                                                                                                                                                                                                        Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata

                                                                                                                                                                                                                                                        Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                                        On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                                                                                                        Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                                                                        Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                                        DIC Take Home Messages

                                                                                                                                                                                                                                                        Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                                                                                                        Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                                                                                                        DIC

                                                                                                                                                                                                                                                        Thank you Questions

                                                                                                                                                                                                                                                        • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                                                                                                        • Learning Objectives
                                                                                                                                                                                                                                                        • Slide Number 3
                                                                                                                                                                                                                                                        • Slide Number 4
                                                                                                                                                                                                                                                        • Slide Number 5
                                                                                                                                                                                                                                                        • Slide Number 6
                                                                                                                                                                                                                                                        • Slide Number 7
                                                                                                                                                                                                                                                        • Slide Number 8
                                                                                                                                                                                                                                                        • Wound Sealing
                                                                                                                                                                                                                                                        • The Three Steps of Hemostasis
                                                                                                                                                                                                                                                        • Vessel Wall
                                                                                                                                                                                                                                                        • Slide Number 12
                                                                                                                                                                                                                                                        • Slide Number 13
                                                                                                                                                                                                                                                        • Platelet Structure UnactivatedActivated
                                                                                                                                                                                                                                                        • Primary Hemostasis
                                                                                                                                                                                                                                                        • Primary Hemostasis Assays
                                                                                                                                                                                                                                                        • Slide Number 17
                                                                                                                                                                                                                                                        • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                                                                                                        • Slide Number 19
                                                                                                                                                                                                                                                        • Coagulation factors
                                                                                                                                                                                                                                                        • Coagulation Assay Mechanisms
                                                                                                                                                                                                                                                        • Slide Number 22
                                                                                                                                                                                                                                                        • Fibrin Formation
                                                                                                                                                                                                                                                        • Slide Number 24
                                                                                                                                                                                                                                                        • Fibrinolysis Overview
                                                                                                                                                                                                                                                        • Fibrinolysis Overview
                                                                                                                                                                                                                                                        • Slide Number 27
                                                                                                                                                                                                                                                        • Fibrinolysis Releases D-dimers
                                                                                                                                                                                                                                                        • Basic Pathophysiology of DIC
                                                                                                                                                                                                                                                        • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                                                                                                        • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                                                                                                        • Clinical Conditions Associated With DIC
                                                                                                                                                                                                                                                        • Frequency of DIC in Selected Disease States
                                                                                                                                                                                                                                                        • Underlying Diseases in DIC Patients
                                                                                                                                                                                                                                                        • Slide Number 36
                                                                                                                                                                                                                                                        • Slide Number 37
                                                                                                                                                                                                                                                        • Slide Number 38
                                                                                                                                                                                                                                                        • Slide Number 39
                                                                                                                                                                                                                                                        • Pathophysiology of DIC
                                                                                                                                                                                                                                                        • Pathogenesis of DIC in Sepsis
                                                                                                                                                                                                                                                        • Host Response in Severe Sepsis
                                                                                                                                                                                                                                                        • Organ Failure in Severe Sepsis
                                                                                                                                                                                                                                                        • Mechanism of DIC in Organ Failure
                                                                                                                                                                                                                                                        • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                                                                                                        • Slide Number 47
                                                                                                                                                                                                                                                        • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                                                                                                        • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                                                                                                        • Mechanism of DIC
                                                                                                                                                                                                                                                        • Pathophysiology of DIC
                                                                                                                                                                                                                                                        • Pathophysiology of DIC - Mechanism
                                                                                                                                                                                                                                                        • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                                                                                                        • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                                                                                                        • Pathophysiology of Overt DIC
                                                                                                                                                                                                                                                        • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                                                                                                        • Slide Number 57
                                                                                                                                                                                                                                                        • Slide Number 58
                                                                                                                                                                                                                                                        • Slide Number 59
                                                                                                                                                                                                                                                        • Slide Number 60
                                                                                                                                                                                                                                                        • Slide Number 61
                                                                                                                                                                                                                                                        • BREAK
                                                                                                                                                                                                                                                        • Diagnostic and Management Approach for DIC
                                                                                                                                                                                                                                                        • Diagnosis of DIC
                                                                                                                                                                                                                                                        • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                                                                                                        • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                                                                                                        • Slide Number 67
                                                                                                                                                                                                                                                        • Slide Number 68
                                                                                                                                                                                                                                                        • British Journal of Haematology Overt DIC Score
                                                                                                                                                                                                                                                        • Slide Number 70
                                                                                                                                                                                                                                                        • Slide Number 71
                                                                                                                                                                                                                                                        • Slide Number 72
                                                                                                                                                                                                                                                        • Slide Number 73
                                                                                                                                                                                                                                                        • DIC Management Goals
                                                                                                                                                                                                                                                        • DIC Management and Treatment
                                                                                                                                                                                                                                                        • DIC Management Strategies
                                                                                                                                                                                                                                                        • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                                                                                                        • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                                                                                                        • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                                                                                                        • D-dimer FDPs and DIC
                                                                                                                                                                                                                                                        • D-Dimer and FDPs in DIC
                                                                                                                                                                                                                                                        • Follow Up of DIC State of Disease
                                                                                                                                                                                                                                                        • FMD-Dimer in DIC Major Differences
                                                                                                                                                                                                                                                        • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                                                                                                        • Slide Number 85
                                                                                                                                                                                                                                                        • Slide Number 86
                                                                                                                                                                                                                                                        • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                                                                                                        • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                        • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                        • Slide Number 94
                                                                                                                                                                                                                                                        • Slide Number 95
                                                                                                                                                                                                                                                        • Slide Number 96
                                                                                                                                                                                                                                                        • Slide Number 97
                                                                                                                                                                                                                                                        • Slide Number 98
                                                                                                                                                                                                                                                        • Slide Number 99
                                                                                                                                                                                                                                                        • DIC Case Studies
                                                                                                                                                                                                                                                        • Case Study 1 - Presentation
                                                                                                                                                                                                                                                        • Case Study 1 ndash Lab Results
                                                                                                                                                                                                                                                        • Case Study 1 ndash Microscopy
                                                                                                                                                                                                                                                        • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                                                                                                        • Slide Number 105
                                                                                                                                                                                                                                                        • Slide Number 106
                                                                                                                                                                                                                                                        • Slide Number 107
                                                                                                                                                                                                                                                        • Slide Number 108
                                                                                                                                                                                                                                                        • Slide Number 109
                                                                                                                                                                                                                                                        • Slide Number 110
                                                                                                                                                                                                                                                        • Slide Number 111
                                                                                                                                                                                                                                                        • Slide Number 112
                                                                                                                                                                                                                                                        • Slide Number 113
                                                                                                                                                                                                                                                        • Slide Number 114
                                                                                                                                                                                                                                                        • Slide Number 115
                                                                                                                                                                                                                                                        • Slide Number 116
                                                                                                                                                                                                                                                        • Slide Number 117
                                                                                                                                                                                                                                                        • Slide Number 118
                                                                                                                                                                                                                                                        • Slide Number 119
                                                                                                                                                                                                                                                        • Slide Number 120
                                                                                                                                                                                                                                                        • Slide Number 121
                                                                                                                                                                                                                                                        • Slide Number 122
                                                                                                                                                                                                                                                        • Slide Number 123
                                                                                                                                                                                                                                                        • Slide Number 124
                                                                                                                                                                                                                                                        • Slide Number 125
                                                                                                                                                                                                                                                        • DIC Take Home Messages
                                                                                                                                                                                                                                                        • Slide Number 127
                                                                                                                                                                                                                                                        • Slide Number 128

                                                                                                                                                                                                                                                          On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away

                                                                                                                                                                                                                                                          Case Study 7 ndash Diagnosis and Treatment

                                                                                                                                                                                                                                                          Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80

                                                                                                                                                                                                                                                          DIC Take Home Messages

                                                                                                                                                                                                                                                          Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                                                                                                          Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                                                                                                          DIC

                                                                                                                                                                                                                                                          Thank you Questions

                                                                                                                                                                                                                                                          • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                                                                                                          • Learning Objectives
                                                                                                                                                                                                                                                          • Slide Number 3
                                                                                                                                                                                                                                                          • Slide Number 4
                                                                                                                                                                                                                                                          • Slide Number 5
                                                                                                                                                                                                                                                          • Slide Number 6
                                                                                                                                                                                                                                                          • Slide Number 7
                                                                                                                                                                                                                                                          • Slide Number 8
                                                                                                                                                                                                                                                          • Wound Sealing
                                                                                                                                                                                                                                                          • The Three Steps of Hemostasis
                                                                                                                                                                                                                                                          • Vessel Wall
                                                                                                                                                                                                                                                          • Slide Number 12
                                                                                                                                                                                                                                                          • Slide Number 13
                                                                                                                                                                                                                                                          • Platelet Structure UnactivatedActivated
                                                                                                                                                                                                                                                          • Primary Hemostasis
                                                                                                                                                                                                                                                          • Primary Hemostasis Assays
                                                                                                                                                                                                                                                          • Slide Number 17
                                                                                                                                                                                                                                                          • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                                                                                                          • Slide Number 19
                                                                                                                                                                                                                                                          • Coagulation factors
                                                                                                                                                                                                                                                          • Coagulation Assay Mechanisms
                                                                                                                                                                                                                                                          • Slide Number 22
                                                                                                                                                                                                                                                          • Fibrin Formation
                                                                                                                                                                                                                                                          • Slide Number 24
                                                                                                                                                                                                                                                          • Fibrinolysis Overview
                                                                                                                                                                                                                                                          • Fibrinolysis Overview
                                                                                                                                                                                                                                                          • Slide Number 27
                                                                                                                                                                                                                                                          • Fibrinolysis Releases D-dimers
                                                                                                                                                                                                                                                          • Basic Pathophysiology of DIC
                                                                                                                                                                                                                                                          • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                                                                                                          • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                                                                                                          • Clinical Conditions Associated With DIC
                                                                                                                                                                                                                                                          • Frequency of DIC in Selected Disease States
                                                                                                                                                                                                                                                          • Underlying Diseases in DIC Patients
                                                                                                                                                                                                                                                          • Slide Number 36
                                                                                                                                                                                                                                                          • Slide Number 37
                                                                                                                                                                                                                                                          • Slide Number 38
                                                                                                                                                                                                                                                          • Slide Number 39
                                                                                                                                                                                                                                                          • Pathophysiology of DIC
                                                                                                                                                                                                                                                          • Pathogenesis of DIC in Sepsis
                                                                                                                                                                                                                                                          • Host Response in Severe Sepsis
                                                                                                                                                                                                                                                          • Organ Failure in Severe Sepsis
                                                                                                                                                                                                                                                          • Mechanism of DIC in Organ Failure
                                                                                                                                                                                                                                                          • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                                                                                                          • Slide Number 47
                                                                                                                                                                                                                                                          • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                                                                                                          • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                                                                                                          • Mechanism of DIC
                                                                                                                                                                                                                                                          • Pathophysiology of DIC
                                                                                                                                                                                                                                                          • Pathophysiology of DIC - Mechanism
                                                                                                                                                                                                                                                          • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                                                                                                          • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                                                                                                          • Pathophysiology of Overt DIC
                                                                                                                                                                                                                                                          • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                                                                                                          • Slide Number 57
                                                                                                                                                                                                                                                          • Slide Number 58
                                                                                                                                                                                                                                                          • Slide Number 59
                                                                                                                                                                                                                                                          • Slide Number 60
                                                                                                                                                                                                                                                          • Slide Number 61
                                                                                                                                                                                                                                                          • BREAK
                                                                                                                                                                                                                                                          • Diagnostic and Management Approach for DIC
                                                                                                                                                                                                                                                          • Diagnosis of DIC
                                                                                                                                                                                                                                                          • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                                                                                                          • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                                                                                                          • Slide Number 67
                                                                                                                                                                                                                                                          • Slide Number 68
                                                                                                                                                                                                                                                          • British Journal of Haematology Overt DIC Score
                                                                                                                                                                                                                                                          • Slide Number 70
                                                                                                                                                                                                                                                          • Slide Number 71
                                                                                                                                                                                                                                                          • Slide Number 72
                                                                                                                                                                                                                                                          • Slide Number 73
                                                                                                                                                                                                                                                          • DIC Management Goals
                                                                                                                                                                                                                                                          • DIC Management and Treatment
                                                                                                                                                                                                                                                          • DIC Management Strategies
                                                                                                                                                                                                                                                          • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                                                                                                          • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                                                                                                          • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                                                                                                          • D-dimer FDPs and DIC
                                                                                                                                                                                                                                                          • D-Dimer and FDPs in DIC
                                                                                                                                                                                                                                                          • Follow Up of DIC State of Disease
                                                                                                                                                                                                                                                          • FMD-Dimer in DIC Major Differences
                                                                                                                                                                                                                                                          • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                                                                                                          • Slide Number 85
                                                                                                                                                                                                                                                          • Slide Number 86
                                                                                                                                                                                                                                                          • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                                                                                                          • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                          • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                          • Slide Number 94
                                                                                                                                                                                                                                                          • Slide Number 95
                                                                                                                                                                                                                                                          • Slide Number 96
                                                                                                                                                                                                                                                          • Slide Number 97
                                                                                                                                                                                                                                                          • Slide Number 98
                                                                                                                                                                                                                                                          • Slide Number 99
                                                                                                                                                                                                                                                          • DIC Case Studies
                                                                                                                                                                                                                                                          • Case Study 1 - Presentation
                                                                                                                                                                                                                                                          • Case Study 1 ndash Lab Results
                                                                                                                                                                                                                                                          • Case Study 1 ndash Microscopy
                                                                                                                                                                                                                                                          • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                                                                                                          • Slide Number 105
                                                                                                                                                                                                                                                          • Slide Number 106
                                                                                                                                                                                                                                                          • Slide Number 107
                                                                                                                                                                                                                                                          • Slide Number 108
                                                                                                                                                                                                                                                          • Slide Number 109
                                                                                                                                                                                                                                                          • Slide Number 110
                                                                                                                                                                                                                                                          • Slide Number 111
                                                                                                                                                                                                                                                          • Slide Number 112
                                                                                                                                                                                                                                                          • Slide Number 113
                                                                                                                                                                                                                                                          • Slide Number 114
                                                                                                                                                                                                                                                          • Slide Number 115
                                                                                                                                                                                                                                                          • Slide Number 116
                                                                                                                                                                                                                                                          • Slide Number 117
                                                                                                                                                                                                                                                          • Slide Number 118
                                                                                                                                                                                                                                                          • Slide Number 119
                                                                                                                                                                                                                                                          • Slide Number 120
                                                                                                                                                                                                                                                          • Slide Number 121
                                                                                                                                                                                                                                                          • Slide Number 122
                                                                                                                                                                                                                                                          • Slide Number 123
                                                                                                                                                                                                                                                          • Slide Number 124
                                                                                                                                                                                                                                                          • Slide Number 125
                                                                                                                                                                                                                                                          • DIC Take Home Messages
                                                                                                                                                                                                                                                          • Slide Number 127
                                                                                                                                                                                                                                                          • Slide Number 128

                                                                                                                                                                                                                                                            DIC Take Home Messages

                                                                                                                                                                                                                                                            Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation

                                                                                                                                                                                                                                                            Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers

                                                                                                                                                                                                                                                            DIC

                                                                                                                                                                                                                                                            Thank you Questions

                                                                                                                                                                                                                                                            • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                                                                                                            • Learning Objectives
                                                                                                                                                                                                                                                            • Slide Number 3
                                                                                                                                                                                                                                                            • Slide Number 4
                                                                                                                                                                                                                                                            • Slide Number 5
                                                                                                                                                                                                                                                            • Slide Number 6
                                                                                                                                                                                                                                                            • Slide Number 7
                                                                                                                                                                                                                                                            • Slide Number 8
                                                                                                                                                                                                                                                            • Wound Sealing
                                                                                                                                                                                                                                                            • The Three Steps of Hemostasis
                                                                                                                                                                                                                                                            • Vessel Wall
                                                                                                                                                                                                                                                            • Slide Number 12
                                                                                                                                                                                                                                                            • Slide Number 13
                                                                                                                                                                                                                                                            • Platelet Structure UnactivatedActivated
                                                                                                                                                                                                                                                            • Primary Hemostasis
                                                                                                                                                                                                                                                            • Primary Hemostasis Assays
                                                                                                                                                                                                                                                            • Slide Number 17
                                                                                                                                                                                                                                                            • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                                                                                                            • Slide Number 19
                                                                                                                                                                                                                                                            • Coagulation factors
                                                                                                                                                                                                                                                            • Coagulation Assay Mechanisms
                                                                                                                                                                                                                                                            • Slide Number 22
                                                                                                                                                                                                                                                            • Fibrin Formation
                                                                                                                                                                                                                                                            • Slide Number 24
                                                                                                                                                                                                                                                            • Fibrinolysis Overview
                                                                                                                                                                                                                                                            • Fibrinolysis Overview
                                                                                                                                                                                                                                                            • Slide Number 27
                                                                                                                                                                                                                                                            • Fibrinolysis Releases D-dimers
                                                                                                                                                                                                                                                            • Basic Pathophysiology of DIC
                                                                                                                                                                                                                                                            • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                                                                                                            • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                                                                                                            • Clinical Conditions Associated With DIC
                                                                                                                                                                                                                                                            • Frequency of DIC in Selected Disease States
                                                                                                                                                                                                                                                            • Underlying Diseases in DIC Patients
                                                                                                                                                                                                                                                            • Slide Number 36
                                                                                                                                                                                                                                                            • Slide Number 37
                                                                                                                                                                                                                                                            • Slide Number 38
                                                                                                                                                                                                                                                            • Slide Number 39
                                                                                                                                                                                                                                                            • Pathophysiology of DIC
                                                                                                                                                                                                                                                            • Pathogenesis of DIC in Sepsis
                                                                                                                                                                                                                                                            • Host Response in Severe Sepsis
                                                                                                                                                                                                                                                            • Organ Failure in Severe Sepsis
                                                                                                                                                                                                                                                            • Mechanism of DIC in Organ Failure
                                                                                                                                                                                                                                                            • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                                                                                                            • Slide Number 47
                                                                                                                                                                                                                                                            • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                                                                                                            • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                                                                                                            • Mechanism of DIC
                                                                                                                                                                                                                                                            • Pathophysiology of DIC
                                                                                                                                                                                                                                                            • Pathophysiology of DIC - Mechanism
                                                                                                                                                                                                                                                            • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                                                                                                            • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                                                                                                            • Pathophysiology of Overt DIC
                                                                                                                                                                                                                                                            • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                                                                                                            • Slide Number 57
                                                                                                                                                                                                                                                            • Slide Number 58
                                                                                                                                                                                                                                                            • Slide Number 59
                                                                                                                                                                                                                                                            • Slide Number 60
                                                                                                                                                                                                                                                            • Slide Number 61
                                                                                                                                                                                                                                                            • BREAK
                                                                                                                                                                                                                                                            • Diagnostic and Management Approach for DIC
                                                                                                                                                                                                                                                            • Diagnosis of DIC
                                                                                                                                                                                                                                                            • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                                                                                                            • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                                                                                                            • Slide Number 67
                                                                                                                                                                                                                                                            • Slide Number 68
                                                                                                                                                                                                                                                            • British Journal of Haematology Overt DIC Score
                                                                                                                                                                                                                                                            • Slide Number 70
                                                                                                                                                                                                                                                            • Slide Number 71
                                                                                                                                                                                                                                                            • Slide Number 72
                                                                                                                                                                                                                                                            • Slide Number 73
                                                                                                                                                                                                                                                            • DIC Management Goals
                                                                                                                                                                                                                                                            • DIC Management and Treatment
                                                                                                                                                                                                                                                            • DIC Management Strategies
                                                                                                                                                                                                                                                            • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                                                                                                            • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                                                                                                            • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                                                                                                            • D-dimer FDPs and DIC
                                                                                                                                                                                                                                                            • D-Dimer and FDPs in DIC
                                                                                                                                                                                                                                                            • Follow Up of DIC State of Disease
                                                                                                                                                                                                                                                            • FMD-Dimer in DIC Major Differences
                                                                                                                                                                                                                                                            • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                                                                                                            • Slide Number 85
                                                                                                                                                                                                                                                            • Slide Number 86
                                                                                                                                                                                                                                                            • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                                                                                                            • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                            • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                            • Slide Number 94
                                                                                                                                                                                                                                                            • Slide Number 95
                                                                                                                                                                                                                                                            • Slide Number 96
                                                                                                                                                                                                                                                            • Slide Number 97
                                                                                                                                                                                                                                                            • Slide Number 98
                                                                                                                                                                                                                                                            • Slide Number 99
                                                                                                                                                                                                                                                            • DIC Case Studies
                                                                                                                                                                                                                                                            • Case Study 1 - Presentation
                                                                                                                                                                                                                                                            • Case Study 1 ndash Lab Results
                                                                                                                                                                                                                                                            • Case Study 1 ndash Microscopy
                                                                                                                                                                                                                                                            • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                                                                                                            • Slide Number 105
                                                                                                                                                                                                                                                            • Slide Number 106
                                                                                                                                                                                                                                                            • Slide Number 107
                                                                                                                                                                                                                                                            • Slide Number 108
                                                                                                                                                                                                                                                            • Slide Number 109
                                                                                                                                                                                                                                                            • Slide Number 110
                                                                                                                                                                                                                                                            • Slide Number 111
                                                                                                                                                                                                                                                            • Slide Number 112
                                                                                                                                                                                                                                                            • Slide Number 113
                                                                                                                                                                                                                                                            • Slide Number 114
                                                                                                                                                                                                                                                            • Slide Number 115
                                                                                                                                                                                                                                                            • Slide Number 116
                                                                                                                                                                                                                                                            • Slide Number 117
                                                                                                                                                                                                                                                            • Slide Number 118
                                                                                                                                                                                                                                                            • Slide Number 119
                                                                                                                                                                                                                                                            • Slide Number 120
                                                                                                                                                                                                                                                            • Slide Number 121
                                                                                                                                                                                                                                                            • Slide Number 122
                                                                                                                                                                                                                                                            • Slide Number 123
                                                                                                                                                                                                                                                            • Slide Number 124
                                                                                                                                                                                                                                                            • Slide Number 125
                                                                                                                                                                                                                                                            • DIC Take Home Messages
                                                                                                                                                                                                                                                            • Slide Number 127
                                                                                                                                                                                                                                                            • Slide Number 128

                                                                                                                                                                                                                                                              DIC

                                                                                                                                                                                                                                                              Thank you Questions

                                                                                                                                                                                                                                                              • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                                                                                                              • Learning Objectives
                                                                                                                                                                                                                                                              • Slide Number 3
                                                                                                                                                                                                                                                              • Slide Number 4
                                                                                                                                                                                                                                                              • Slide Number 5
                                                                                                                                                                                                                                                              • Slide Number 6
                                                                                                                                                                                                                                                              • Slide Number 7
                                                                                                                                                                                                                                                              • Slide Number 8
                                                                                                                                                                                                                                                              • Wound Sealing
                                                                                                                                                                                                                                                              • The Three Steps of Hemostasis
                                                                                                                                                                                                                                                              • Vessel Wall
                                                                                                                                                                                                                                                              • Slide Number 12
                                                                                                                                                                                                                                                              • Slide Number 13
                                                                                                                                                                                                                                                              • Platelet Structure UnactivatedActivated
                                                                                                                                                                                                                                                              • Primary Hemostasis
                                                                                                                                                                                                                                                              • Primary Hemostasis Assays
                                                                                                                                                                                                                                                              • Slide Number 17
                                                                                                                                                                                                                                                              • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                                                                                                              • Slide Number 19
                                                                                                                                                                                                                                                              • Coagulation factors
                                                                                                                                                                                                                                                              • Coagulation Assay Mechanisms
                                                                                                                                                                                                                                                              • Slide Number 22
                                                                                                                                                                                                                                                              • Fibrin Formation
                                                                                                                                                                                                                                                              • Slide Number 24
                                                                                                                                                                                                                                                              • Fibrinolysis Overview
                                                                                                                                                                                                                                                              • Fibrinolysis Overview
                                                                                                                                                                                                                                                              • Slide Number 27
                                                                                                                                                                                                                                                              • Fibrinolysis Releases D-dimers
                                                                                                                                                                                                                                                              • Basic Pathophysiology of DIC
                                                                                                                                                                                                                                                              • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                                                                                                              • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                                                                                                              • Clinical Conditions Associated With DIC
                                                                                                                                                                                                                                                              • Frequency of DIC in Selected Disease States
                                                                                                                                                                                                                                                              • Underlying Diseases in DIC Patients
                                                                                                                                                                                                                                                              • Slide Number 36
                                                                                                                                                                                                                                                              • Slide Number 37
                                                                                                                                                                                                                                                              • Slide Number 38
                                                                                                                                                                                                                                                              • Slide Number 39
                                                                                                                                                                                                                                                              • Pathophysiology of DIC
                                                                                                                                                                                                                                                              • Pathogenesis of DIC in Sepsis
                                                                                                                                                                                                                                                              • Host Response in Severe Sepsis
                                                                                                                                                                                                                                                              • Organ Failure in Severe Sepsis
                                                                                                                                                                                                                                                              • Mechanism of DIC in Organ Failure
                                                                                                                                                                                                                                                              • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                                                                                                              • Slide Number 47
                                                                                                                                                                                                                                                              • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                                                                                                              • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                                                                                                              • Mechanism of DIC
                                                                                                                                                                                                                                                              • Pathophysiology of DIC
                                                                                                                                                                                                                                                              • Pathophysiology of DIC - Mechanism
                                                                                                                                                                                                                                                              • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                                                                                                              • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                                                                                                              • Pathophysiology of Overt DIC
                                                                                                                                                                                                                                                              • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                                                                                                              • Slide Number 57
                                                                                                                                                                                                                                                              • Slide Number 58
                                                                                                                                                                                                                                                              • Slide Number 59
                                                                                                                                                                                                                                                              • Slide Number 60
                                                                                                                                                                                                                                                              • Slide Number 61
                                                                                                                                                                                                                                                              • BREAK
                                                                                                                                                                                                                                                              • Diagnostic and Management Approach for DIC
                                                                                                                                                                                                                                                              • Diagnosis of DIC
                                                                                                                                                                                                                                                              • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                                                                                                              • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                                                                                                              • Slide Number 67
                                                                                                                                                                                                                                                              • Slide Number 68
                                                                                                                                                                                                                                                              • British Journal of Haematology Overt DIC Score
                                                                                                                                                                                                                                                              • Slide Number 70
                                                                                                                                                                                                                                                              • Slide Number 71
                                                                                                                                                                                                                                                              • Slide Number 72
                                                                                                                                                                                                                                                              • Slide Number 73
                                                                                                                                                                                                                                                              • DIC Management Goals
                                                                                                                                                                                                                                                              • DIC Management and Treatment
                                                                                                                                                                                                                                                              • DIC Management Strategies
                                                                                                                                                                                                                                                              • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                                                                                                              • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                                                                                                              • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                                                                                                              • D-dimer FDPs and DIC
                                                                                                                                                                                                                                                              • D-Dimer and FDPs in DIC
                                                                                                                                                                                                                                                              • Follow Up of DIC State of Disease
                                                                                                                                                                                                                                                              • FMD-Dimer in DIC Major Differences
                                                                                                                                                                                                                                                              • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                                                                                                              • Slide Number 85
                                                                                                                                                                                                                                                              • Slide Number 86
                                                                                                                                                                                                                                                              • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                                                                                                              • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                              • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                              • Slide Number 94
                                                                                                                                                                                                                                                              • Slide Number 95
                                                                                                                                                                                                                                                              • Slide Number 96
                                                                                                                                                                                                                                                              • Slide Number 97
                                                                                                                                                                                                                                                              • Slide Number 98
                                                                                                                                                                                                                                                              • Slide Number 99
                                                                                                                                                                                                                                                              • DIC Case Studies
                                                                                                                                                                                                                                                              • Case Study 1 - Presentation
                                                                                                                                                                                                                                                              • Case Study 1 ndash Lab Results
                                                                                                                                                                                                                                                              • Case Study 1 ndash Microscopy
                                                                                                                                                                                                                                                              • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                                                                                                              • Slide Number 105
                                                                                                                                                                                                                                                              • Slide Number 106
                                                                                                                                                                                                                                                              • Slide Number 107
                                                                                                                                                                                                                                                              • Slide Number 108
                                                                                                                                                                                                                                                              • Slide Number 109
                                                                                                                                                                                                                                                              • Slide Number 110
                                                                                                                                                                                                                                                              • Slide Number 111
                                                                                                                                                                                                                                                              • Slide Number 112
                                                                                                                                                                                                                                                              • Slide Number 113
                                                                                                                                                                                                                                                              • Slide Number 114
                                                                                                                                                                                                                                                              • Slide Number 115
                                                                                                                                                                                                                                                              • Slide Number 116
                                                                                                                                                                                                                                                              • Slide Number 117
                                                                                                                                                                                                                                                              • Slide Number 118
                                                                                                                                                                                                                                                              • Slide Number 119
                                                                                                                                                                                                                                                              • Slide Number 120
                                                                                                                                                                                                                                                              • Slide Number 121
                                                                                                                                                                                                                                                              • Slide Number 122
                                                                                                                                                                                                                                                              • Slide Number 123
                                                                                                                                                                                                                                                              • Slide Number 124
                                                                                                                                                                                                                                                              • Slide Number 125
                                                                                                                                                                                                                                                              • DIC Take Home Messages
                                                                                                                                                                                                                                                              • Slide Number 127
                                                                                                                                                                                                                                                              • Slide Number 128

                                                                                                                                                                                                                                                                Thank you Questions

                                                                                                                                                                                                                                                                • Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
                                                                                                                                                                                                                                                                • Learning Objectives
                                                                                                                                                                                                                                                                • Slide Number 3
                                                                                                                                                                                                                                                                • Slide Number 4
                                                                                                                                                                                                                                                                • Slide Number 5
                                                                                                                                                                                                                                                                • Slide Number 6
                                                                                                                                                                                                                                                                • Slide Number 7
                                                                                                                                                                                                                                                                • Slide Number 8
                                                                                                                                                                                                                                                                • Wound Sealing
                                                                                                                                                                                                                                                                • The Three Steps of Hemostasis
                                                                                                                                                                                                                                                                • Vessel Wall
                                                                                                                                                                                                                                                                • Slide Number 12
                                                                                                                                                                                                                                                                • Slide Number 13
                                                                                                                                                                                                                                                                • Platelet Structure UnactivatedActivated
                                                                                                                                                                                                                                                                • Primary Hemostasis
                                                                                                                                                                                                                                                                • Primary Hemostasis Assays
                                                                                                                                                                                                                                                                • Slide Number 17
                                                                                                                                                                                                                                                                • Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
                                                                                                                                                                                                                                                                • Slide Number 19
                                                                                                                                                                                                                                                                • Coagulation factors
                                                                                                                                                                                                                                                                • Coagulation Assay Mechanisms
                                                                                                                                                                                                                                                                • Slide Number 22
                                                                                                                                                                                                                                                                • Fibrin Formation
                                                                                                                                                                                                                                                                • Slide Number 24
                                                                                                                                                                                                                                                                • Fibrinolysis Overview
                                                                                                                                                                                                                                                                • Fibrinolysis Overview
                                                                                                                                                                                                                                                                • Slide Number 27
                                                                                                                                                                                                                                                                • Fibrinolysis Releases D-dimers
                                                                                                                                                                                                                                                                • Basic Pathophysiology of DIC
                                                                                                                                                                                                                                                                • Disseminated Intravascular Coagulation (DIC)
                                                                                                                                                                                                                                                                • Purpura Fulminans with DIC Due to Meningococcal Sepsis
                                                                                                                                                                                                                                                                • Clinical Conditions Associated With DIC
                                                                                                                                                                                                                                                                • Frequency of DIC in Selected Disease States
                                                                                                                                                                                                                                                                • Underlying Diseases in DIC Patients
                                                                                                                                                                                                                                                                • Slide Number 36
                                                                                                                                                                                                                                                                • Slide Number 37
                                                                                                                                                                                                                                                                • Slide Number 38
                                                                                                                                                                                                                                                                • Slide Number 39
                                                                                                                                                                                                                                                                • Pathophysiology of DIC
                                                                                                                                                                                                                                                                • Pathogenesis of DIC in Sepsis
                                                                                                                                                                                                                                                                • Host Response in Severe Sepsis
                                                                                                                                                                                                                                                                • Organ Failure in Severe Sepsis
                                                                                                                                                                                                                                                                • Mechanism of DIC in Organ Failure
                                                                                                                                                                                                                                                                • Interaction of Inflammation and Coagulation in Sepsis
                                                                                                                                                                                                                                                                • Slide Number 47
                                                                                                                                                                                                                                                                • Diverse and Opposing Effects of Thrombin
                                                                                                                                                                                                                                                                • Coagulation and Fibrinolysis in DIC
                                                                                                                                                                                                                                                                • Mechanism of DIC
                                                                                                                                                                                                                                                                • Pathophysiology of DIC
                                                                                                                                                                                                                                                                • Pathophysiology of DIC - Mechanism
                                                                                                                                                                                                                                                                • Pathophysiology of DIC ndash 2 Types of Clinical pictures
                                                                                                                                                                                                                                                                • Sub-Acute and Non-Overt DIC Clinical Findings
                                                                                                                                                                                                                                                                • Pathophysiology of Overt DIC
                                                                                                                                                                                                                                                                • Physiopathology of DIC ndash Overt DIC Findings
                                                                                                                                                                                                                                                                • Slide Number 57
                                                                                                                                                                                                                                                                • Slide Number 58
                                                                                                                                                                                                                                                                • Slide Number 59
                                                                                                                                                                                                                                                                • Slide Number 60
                                                                                                                                                                                                                                                                • Slide Number 61
                                                                                                                                                                                                                                                                • BREAK
                                                                                                                                                                                                                                                                • Diagnostic and Management Approach for DIC
                                                                                                                                                                                                                                                                • Diagnosis of DIC
                                                                                                                                                                                                                                                                • Lab Diagnosis of DIC ndash Markers of Factor Consumption
                                                                                                                                                                                                                                                                • Lab Diagnosis of DIC ndash Screening Tests
                                                                                                                                                                                                                                                                • Slide Number 67
                                                                                                                                                                                                                                                                • Slide Number 68
                                                                                                                                                                                                                                                                • British Journal of Haematology Overt DIC Score
                                                                                                                                                                                                                                                                • Slide Number 70
                                                                                                                                                                                                                                                                • Slide Number 71
                                                                                                                                                                                                                                                                • Slide Number 72
                                                                                                                                                                                                                                                                • Slide Number 73
                                                                                                                                                                                                                                                                • DIC Management Goals
                                                                                                                                                                                                                                                                • DIC Management and Treatment
                                                                                                                                                                                                                                                                • DIC Management Strategies
                                                                                                                                                                                                                                                                • Anticoagulant Factor Concentrate Treatment
                                                                                                                                                                                                                                                                • Anticoagulant Factor Concentrate Treatment Trials
                                                                                                                                                                                                                                                                • Markers of Thrombin amp Plasmin Generation in DIC
                                                                                                                                                                                                                                                                • D-dimer FDPs and DIC
                                                                                                                                                                                                                                                                • D-Dimer and FDPs in DIC
                                                                                                                                                                                                                                                                • Follow Up of DIC State of Disease
                                                                                                                                                                                                                                                                • FMD-Dimer in DIC Major Differences
                                                                                                                                                                                                                                                                • of Abnormal Results in Patients with Confirmed and Suspected DIC
                                                                                                                                                                                                                                                                • Slide Number 85
                                                                                                                                                                                                                                                                • Slide Number 86
                                                                                                                                                                                                                                                                • Comparing an Automated FM vs Manual FSP Test
                                                                                                                                                                                                                                                                • Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                                • Diagnostic Performance of FM and D-dimer in DIC
                                                                                                                                                                                                                                                                • Slide Number 94
                                                                                                                                                                                                                                                                • Slide Number 95
                                                                                                                                                                                                                                                                • Slide Number 96
                                                                                                                                                                                                                                                                • Slide Number 97
                                                                                                                                                                                                                                                                • Slide Number 98
                                                                                                                                                                                                                                                                • Slide Number 99
                                                                                                                                                                                                                                                                • DIC Case Studies
                                                                                                                                                                                                                                                                • Case Study 1 - Presentation
                                                                                                                                                                                                                                                                • Case Study 1 ndash Lab Results
                                                                                                                                                                                                                                                                • Case Study 1 ndash Microscopy
                                                                                                                                                                                                                                                                • Case Study 1 ndash Diagnosis and Therapy
                                                                                                                                                                                                                                                                • Slide Number 105
                                                                                                                                                                                                                                                                • Slide Number 106
                                                                                                                                                                                                                                                                • Slide Number 107
                                                                                                                                                                                                                                                                • Slide Number 108
                                                                                                                                                                                                                                                                • Slide Number 109
                                                                                                                                                                                                                                                                • Slide Number 110
                                                                                                                                                                                                                                                                • Slide Number 111
                                                                                                                                                                                                                                                                • Slide Number 112
                                                                                                                                                                                                                                                                • Slide Number 113
                                                                                                                                                                                                                                                                • Slide Number 114
                                                                                                                                                                                                                                                                • Slide Number 115
                                                                                                                                                                                                                                                                • Slide Number 116
                                                                                                                                                                                                                                                                • Slide Number 117
                                                                                                                                                                                                                                                                • Slide Number 118
                                                                                                                                                                                                                                                                • Slide Number 119
                                                                                                                                                                                                                                                                • Slide Number 120
                                                                                                                                                                                                                                                                • Slide Number 121
                                                                                                                                                                                                                                                                • Slide Number 122
                                                                                                                                                                                                                                                                • Slide Number 123
                                                                                                                                                                                                                                                                • Slide Number 124
                                                                                                                                                                                                                                                                • Slide Number 125
                                                                                                                                                                                                                                                                • DIC Take Home Messages
                                                                                                                                                                                                                                                                • Slide Number 127
                                                                                                                                                                                                                                                                • Slide Number 128

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