Failure of Coagulation MUDr. Tomáš Stopka Ph.D. and colleagues from the Institute of Pathophysiology, Charles University.

Failure ofFailure of CCoagulaoagulationtion

MUDr. Tomáš Stopka Ph.D. MUDr. Tomáš Stopka Ph.D.

and colleagues from the and colleagues from the Institute of Pathophysiology, Institute of Pathophysiology,

Charles UniversityCharles University

PlPlaann

CoagulationCoagulation MethodsMethods

DICDIC TThheraperapyy

PresentationPresentation

I. CoagulationI. CoagulationInitiating the Clotting Process

1. Damaged cells (extrinsic pathway) display a surface protein called tissue factor (TF) that binds to activated Factor 7 (TF-7) to cleave: Factor 10

2. Factor 10 binds and activates Factor 5 (prothrombinase) convertíng prothrombin (also known as Factor II) to thrombin

3. Thrombin proteolytically cleave fibrinogen (Factor I) to fibrin.

4. Factor 13 forms covalent bonds between the soluble fibrin molecules converting them into an insoluble meshwork — the clot.

I. CI. CoagulaoagulationtionAmplifying the Clotting Process

1. The TF-7 complex also activates Factor 9.

2. Factor 9 binds to Factor 8, a protein that circulates in the blood stabilized by another protein, von Willebrand Factor (vWF).

3. Complex 9-8-vW activates more factors: 5,8,10,11

I. CoagulationI. CoagulationLUMEN

Blood clotWALL

Endothelial demageDamaged

endothelial cells display tissue factor

(TF) that binds to activated

Factor 7 (TF-7) to cleave: Factor 10

The intrinsic

cascade is initiated

when contact is

made between

blood and exposed

endothelial cell

surfaces.

I. CoagulationI. Coagulation Controlling ClottingAntithrombin III inactivates: prothrombin, factor 9,

factor 10

Protein C and its cofactor Protein S together inhibit thrombin formation by inactivating Factor 5 and by inactivating Factor 8.

Inherited deficiency (mutations) of Protein C or Protein S (or FV, Leiden)= thrombophilia

Vitamin K is a cofactor needed for the synthesis (in the liver) of

factors 2 (prothrombin), 7, 9, and 10, proteins C and SDeficiency of Vitamin K predisposes to bleeding.

Conversely, blocking the action of vitamin K helps to prevent inappropriate clotting.

Heparin binds to and enhances antithrombin III.

Warfarin (aka coumadin) is an effective vitamin K antagonist.

I. CI. Coagulaoagulationtion Dissolving clots

Plasma plasminogen to the fibrin molecules in a clot. Nearby healthy cells release tissue plasminogen activator (TPA), which also binds to fibrin and, activates plasminogen forming plasmin. Plasmin (serine protease) proceeds to digest fibrin, thus dissolving the clot.

I. CoagulationI. CoagulationHEMOCOAGULATION is INTEGRAL PART of INFLAMATORY RESPONSE

PLATELETS PLAZMATIC COAGULATION SYSTEM

VASCULAR WALL

ENDOTHELIUM

I. CI. CoagulaoagulationtionDISORDERS OF HEMOCOAGULATION = THROMBOSIS AND EMBOLISM

THROMBOSIS

IN MICROCIRCULATION

ARTERIAL

VENOUS

EMBOLISM

LUNGS SYSTEMICSIGNS

-TISSUE ISCHEMIA

- HEMODYNAMIC FAILURE

I. CI. Coagulaoagulationtion Deep Venous Thrombosis (DVT)

A) asymptomatic : > 50% Lung Embolism.B) symptomatic: pain (Homans’s sign), oedema,

dicoloration and incr. temperature of the skin

Posthrombotic syndromelatent, 3 - 15 y after DVT: distension of superf. veins, lipodermatosclerosis, varices, ulceration.

Lung embolism (LE)Dyspnoe, tachypnoe, tachykardia, pleuritic chest pain, distension of the jugular veins, hemoptysis, hemodynamic instability, hemodynamic failure or death.

I. CI. CoagulaoagulationtionBLEEDING

SURGERY SMALL, TRAUMATIC- sc., im.injections- Easy bruising

DIFUSEMICROVASCULAR- purpura - petechia, ekchymosis (>3 mm)- organ apoplexia

A) trombocytopeniaB) Desintegration of microvascular intima

Failure of coagulationtraumatic

II. LaboratoryII. Laboratory

Bleeding time (Duke, 1910)standard puncture of the ear lobe (Duke, 1910) 2 - 5 min. prolonged in thrombocytopenia (<20 000/uL) OR vonWillebrand disease

Capillary resistance ( Rumpel, Leede)pressure on the arm 10,5 kPa/10 min petechia > 5 = increased fragility of capillaries. (hereditary purpura e.g. Weber-Rendu-Osler).

BLEEDING TIME and RESISTANCE OF CAPILARS

II. LaboratoryII. Laboratory

Thrombin time

-full blood is activated with thrombin to form fibrin fiber

-used for measurement of fibrinogen levels (DIC)

Basic coagulation methods

II. LaboratoryII. Laboratory

(PLT) – normal 150 - 300 000/uL, for surgery optimum > 100 000 /uL. Thrombocytopenia PLT < 20 000/ uL – spontaneous bleeding and purpura.

(MPV) - normal 6 - 9 fL, incr. hereditary trombocytopathy.

Agregometry – photometric, with addition of activator of platelet aggregation - ADP, thrombin, kolagen. Diagnosis of hereditary trombocytopaty

Flow cytometry - imunologic. Anti PLT antibodies – diagnosis of imune-

mediated trombocytopenia vWf - imunologic or functional tests incl.

ristocetin

Methods for measuring platelets and vWf

II. LaboratoryII. Laboratory

PT – prothrombin time PT (Quickův) APTT - activated partial thromboplastin time

Statim FBG - fibrinogenu plasma levels (normal :2 -

4 g/L). ( FBG acute phase protein) FDP - imunologic measurement of

degradation products of fibri(noge)n (normal: < 1000 ug/L), ELISA or aglutination semiq. methods.

Methods for measuring Coagulation factors

Blood drown into citrate is centrifuged to obtain decalcified plasma

II. LaboratoryII. Laboratory

D-dimer - imunologic measurement of FDP specific for stabilized fibrin (normal < 500 ug/L). Increased D-dimer DVT/PE and DIC.

AT - function test to measure antithrombin activity in plasma (normal 80 - 100% activity of the control plasma). With heparin part of the TAT inhibitory complex, deficiency predispose to thrombophilia or DIC.

Methods for measuring Coagulation factors

II. LaboratoryII. Laboratory

Ethanol test – FDP anti-polymeration effect on fibrin fiber is blocked by ethanol

Euglobulin method of measuring fibrinolytic activityEuglobulin fraction of plasma obtained with acetic acid conatins predominantly plasminogen, in DIC there is more plasmin and so the test is quicker (result of increased fibrinolysis).

Methods for measuring Coagulation

II. LaboratoryII. Laboratory

proteinu C- Act. Protein C resistence, mutation of FV, mutation of protein S

fibrinolytic system- tPA , inhibitor PAI-1, plazminogen, inhibitor alfa2AP

Antifosfolipid antibodies - lupus anticoagulans (LA) : modif. APTT

Individual factors hemofilia A (FVIII), B(FIX), C (FXI)

Methods for measuring Coagulation

II. LaboratoryII. Laboratory

Principle: extrinsic pathway – tissue factor. Blood drawn to citrate and TF is added. with CaCl2. Time is measured until the fibrin fiber is formed.

Normal: PTN= 12 - 15 s

Prolonged PT:, deficiency of FV, vit. K dep: FII, VII, X, deficient FBG, high FDPs

International normalized ratio INR= (PTP/ PTN)ISI ISI = international index of used tromboplastin (usu > 1). (max. therapeutic INR = 4,5)

Protrombin time PT (Quick)

II. LaboratoryII. Laboratory Principle : intrinsic pathway. Blood drawn to citrate

and kaolin (activates inner system) is added with CaCl2. Time is measured until the fibrin fiber is formed.

Normal APTTN = 27 - 35 s

Used: hemophilia, lupus anticoagulans, heparin therapy (1,5x - 2,5 x).

Prolonged APTT: deficient FII,V, X, - F XII, PreK, HMWK, - FXI, FIX , FVIII (hemofilia C, B,A), lupus anticoagulans, low FBG, high FDP.

Shortened APTT: thrombophilia

APTT

II. LaboratoryII. Laboratory

Disorder PLT BT APTT PT TT FBG

Trombocytopenia L P N N N N

Hemofilia A N N P N N N

Hemofilia B N N P N N N

Hemofilia C N N P N N N

vW-disease N P N/P N N N

LA N N P N/P N N

II. LaboratoryII. Laboratory

Disorder PLT BT APTT PT TTFBG

FV-def.

FII-def.

FVII-def.

Vit.Kdef./OA

FBG-def.

HeparinN P/N P N/P P N

N N P P P L

N N P P N N

N N N P N N

N N P P N N

N N P P N N

III.III. DICDIC

DefinitionDefinition  

SecondarySecondary

Disorder of Coagulation with pro-Disorder of Coagulation with pro-thrombotic phase followed by severe thrombotic phase followed by severe bleeding phase (as a result of bleeding phase (as a result of consumption of coagulation factors).consumption of coagulation factors).

III.III. DICDIC

EthiopathogenesisEthiopathogenesis  

Intravascular coagulationIntravascular coagulation

Conditions Associated with Conditions Associated with DICDIC

Heat strokeHeat stroke SepsisSepsis ViremiaViremia PancreatitisPancreatitis Neoplasia (Diffuse and Neoplasia (Diffuse and

local)local) Parasitic InfectionsParasitic Infections Intravascular HemolysisIntravascular Hemolysis Immune-mediated Immune-mediated

DiseasesDiseases Exposure to venom/toxinsExposure to venom/toxins Massive tissue injury Massive tissue injury

(including burns, crush (including burns, crush trauma, and surgical trauma, and surgical procedures)procedures)

ObstetricObstetric ComplicationsComplications Insufficiency of major Insufficiency of major

organs (Liver, Kidney)organs (Liver, Kidney) Diabetes mellitusDiabetes mellitus AcidosisAcidosis PolycythemiaPolycythemia Severe prolonged Severe prolonged

hypotension (including hypotension (including shock)shock)

Severe volume depletionSevere volume depletion Impaired blood flow to a Impaired blood flow to a

major orgamajor organn

What are FDPs and D-What are FDPs and D-dimers and how do they dimers and how do they

relate to DIC?relate to DIC? Activation of the coagulation Activation of the coagulation

cascade results in cascade results in increased increased levels of circulating thrombin levels of circulating thrombin and plasminand plasmin. .

Thrombin cleaves Thrombin cleaves fibrinopeptides A and B from fibrinopeptides A and B from fibrinogen, leaving soluble fibrinogen, leaving soluble fibrin monomersfibrin monomers as the end as the end product (Figure 1).product (Figure 1).

Activation of factor XIII results Activation of factor XIII results in in polymerization of these polymerization of these fibrin monomersfibrin monomers into insoluble into insoluble cross-linked fibrin clots.cross-linked fibrin clots.

•Increased levels of Increased levels of circulating plasmin causes circulating plasmin causes clot lysis and degradation of clot lysis and degradation of fibrinogenfibrinogen and the soluble and the soluble fibrin monomersfibrin monomers..

•Plasmin cleaves fibrinogen Plasmin cleaves fibrinogen into fragments X,Y,D, and E, into fragments X,Y,D, and E, known as known as fibrinogen fibrinogen degradation products degradation products (FDPs).(FDPs).

•Plasmin also cleaves Plasmin also cleaves insoluble cross-linked fibrin insoluble cross-linked fibrin polymers into x-oligomers. polymers into x-oligomers. The main x-oligomers are The main x-oligomers are known as d-dimers.known as d-dimers.

DIC

What are FDPs and D-What are FDPs and D-dimers and how do they dimers and how do they

relate to DIC?relate to DIC?FIBRIN

Monoclonal antibodies have Monoclonal antibodies have been generated which been generated which recognize the recognize the cross-linked cross-linked domain of d-dimers as an domain of d-dimers as an antigenic targetantigenic target. These . These antibodies are used in all antibodies are used in all available d-dimer assays.available d-dimer assays.

Quantitative tests for d-dimers Quantitative tests for d-dimers are available, including are available, including enzymatic immunoassays enzymatic immunoassays (ELISA) and (ELISA) and immunoturbidometric systems. immunoturbidometric systems.

III.III. DICDIC

NORM NORM 

PLT   150 - 300 000 x 10 exp9 /lPLT   150 - 300 000 x 10 exp9 /l APTT   30 - 35 sAPTT   30 - 35 s AT    80 - 140 %AT    80 - 140 % TT    14 - 16 sTT    14 - 16 s FBG   2.5 - 5 g/lFBG   2.5 - 5 g/l FM (ethanol test)   FM (ethanol test)    DD    < 500 ng/mlDD    < 500 ng/ml FDP   FDP   

III.III. DICDIC

DIC DIC 

PLT   lowPLT   low APTT   short or prolonged APTT   short or prolonged AT    low AT    low TT    prolonged TT    prolonged FBG   lowFBG   low FM (etanol test)  positive FM (etanol test)  positive plasminogen  lowplasminogen  low DD    positiveDD    positive FDP   positiveFDP   positive euglobulin lysis norm. - prolongedeuglobulin lysis norm. - prolonged

III.III. DICDIC

PLT PLT FBG FBG DD DD AT AT

Repeat every 3-4h Repeat every 3-4h

III.III. DICDIC

11 HypercoagulationHypercoagulationSilentSilent

22 Hypocoagulation Hypocoagulation Bleeding and thrombosis in Bleeding and thrombosis in

microcirculation microcirculation

33 Massive fibrinolysis Massive fibrinolysis Bleeding and multiorgan failure (MOF)Bleeding and multiorgan failure (MOF)

44 Death Death

Thrombotic Thrombocytopenic Thrombotic Thrombocytopenic PurpuraPurpura

von Willebrand factor protein multimer analysis on agarose gel electrophoresis. Lane 1. - normal plasma. Lane 2. - patient plasma when symptomatic. Multimer pattern is similar to the control plasma. Lane 3. - patient plasma after response to pheresis. Note the presence of ultra-large high molecular weight multimers.

Peripheral smear showing microangiopathic hemolytic features with numerous RBC fragments (helmet cells/schistocytes). Marked thrombocytopenia is evident.

Renal biopsy showing hyaline thrombi in the glomerulus and small arterioles.

Researchers Pinpoint Cause of Deadly Blood-Clotting Researchers Pinpoint Cause of Deadly Blood-Clotting DisorderDisorder

Several earlier studies had implicated a Several earlier studies had implicated a clotting-related protein known as clotting-related protein known as

von Willebrand factor (VWF) in the disordervon Willebrand factor (VWF) in the disorder. These studies found that the . These studies found that the

blood of patients with TTP showed an blood of patients with TTP showed an abnormally large form of the VWF abnormally large form of the VWF

proteinprotein that had not been cleaved into two smaller sizes, as is normally the that had not been cleaved into two smaller sizes, as is normally the

case. Thus, said case. Thus, said GinsburgGinsburg, many scientists believed that a defect in a protein-, many scientists believed that a defect in a protein-

clipping enzyme known as a protease might be responsible for the disorder. clipping enzyme known as a protease might be responsible for the disorder.

One of the keys to identifying the gene mutations that underlie TTP was the development One of the keys to identifying the gene mutations that underlie TTP was the development of a precise assay for detecting VWF protease activity. Han-Mou Tsai, a senior author of of a precise assay for detecting VWF protease activity. Han-Mou Tsai, a senior author of the the NatureNature paper, and colleagues at Montefiore Medical Center and Albert Einstein paper, and colleagues at Montefiore Medical Center and Albert Einstein College of Medicine developed the assay and applied it to blood samples that were College of Medicine developed the assay and applied it to blood samples that were provided by members of provided by members of four families that had an inherited form of TTPfour families that had an inherited form of TTP. The assays . The assays clearly revealed that within these families, those who had TTP showed low VWF protease clearly revealed that within these families, those who had TTP showed low VWF protease activity, while carriers of the disease showed medium levels of protease activity, and activity, while carriers of the disease showed medium levels of protease activity, and unaffected individuals showed normal levels. unaffected individuals showed normal levels.

Using results from the assay as a guide, Gallia G. Levy, lead author of the Using results from the assay as a guide, Gallia G. Levy, lead author of the NatureNature article, article, performed performed linkage analyses of the family members and determined which of known linkage analyses of the family members and determined which of known genomic markers were inherited with the disease genegenomic markers were inherited with the disease gene. These studies enabled her to . These studies enabled her to narrow down the region containing the disease gene to a specific region of chromosome 9. narrow down the region containing the disease gene to a specific region of chromosome 9.

Levy then obtained the full gene sequence and proceeded to test the other patients for Levy then obtained the full gene sequence and proceeded to test the other patients for mutations in the gene, which they named mutations in the gene, which they named ADAMTS13ADAMTS13. Levy subsequently identified a . Levy subsequently identified a dozen mutations in the gene among the patients, accounting for nearly all the cases of dozen mutations in the gene among the patients, accounting for nearly all the cases of TTP. According to Ginsburg, Levy’s findings open the way to understanding how and why TTP. According to Ginsburg, Levy’s findings open the way to understanding how and why the the ADAMTS13ADAMTS13 protease cleaves VWF and how the failure to cleave the protein causes protease cleaves VWF and how the failure to cleave the protein causes diseasedisease. .

III.III. DICDIC

Therapy: Therapy: 

Blockade of activated coagulation Blockade of activated coagulation 

1 Heparin1 Heparin 5-105-10 IU/kg/h IU/kg/h bolus 2500 IU, inf. Up to 10 000 bolus 2500 IU, inf. Up to 10 000

IU/24h IU/24h

LMWH LMWH

III.III. DICDIC

Therapy: Therapy: 

Blockade of activated coagulation Blockade of activated coagulation 

2 AT (Antitrombin III, Kybernin P) 2 AT (Antitrombin III, Kybernin P) If less 60%, target~ 100 - 150% If less 60%, target~ 100 - 150% 500 - 1000 bolus 500 - 1000 bolus KI unknown KI unknown Half life 3-4 d, during sepsis hours Half life 3-4 d, during sepsis hours

III.III. DICDICTherapy: Therapy: 

SubstitutionSubstitution  

3 Fresh frozen plasma3 Fresh frozen plasma 15 ml/kg if APTT more than 1.5 R 15 ml/kg if APTT more than 1.5 R

4 Fibrinogen4 Fibrinogen If less than 1.0 g/l (maximally 2g/24h) If less than 1.0 g/l (maximally 2g/24h) 2 - 4 g in infusion2 - 4 g in infusion

III.III. DICDICTherapy: Therapy: 

SubstitutionSubstitution  

5 5 ErythrocytesErythrocytes

6  PLT6  PLT 1 unit/10kg 1 unit/10kg

III.III. DICDIC

Therapy: Therapy: 

OTHEROTHER  

1 shock1 shock 2  volume2  volume 3 acidobasic and ionts3 acidobasic and ionts 4 ATB4 ATB 5 Surgical5 Surgical

III.III. DICDIC

Acute DICAcute DIC DIAGNOSISDIAGNOSIS

Clinical findingsClinical findings Multiple bleeding sites Multiple bleeding sites Ecchymoses of skin, mucous membranes Ecchymoses of skin, mucous membranes Visceral hemorrhage Visceral hemorrhage Ischemic tissue Ischemic tissue

Laboratory abnormalitiesLaboratory abnormalities Coagulation abnormalities: prolonged prothrombin Coagulation abnormalities: prolonged prothrombin

time, activated partial thromboplastin time, thrombin time, activated partial thromboplastin time, thrombin time; decreased fibrinogen levels; increased levels of time; decreased fibrinogen levels; increased levels of FDP (eg, on testing for FDP, D dimer) FDP (eg, on testing for FDP, D dimer)

Platelet count decreased as a rule but may be falling Platelet count decreased as a rule but may be falling from a higher level yet still be normal from a higher level yet still be normal

Schistocytes on peripheral smear Schistocytes on peripheral smear

Chronic DIC Chronic DIC DIAGNOSISDIAGNOSIS

Clinical findings Clinical findings

Signs of deep venous or arterial thrombosis Signs of deep venous or arterial thrombosis or embolismor embolism

Superficial venous thrombosis, especially Superficial venous thrombosis, especially without varicose veins without varicose veins

Multiple thrombotic sites at the same time Multiple thrombotic sites at the same time

Serial thrombotic episodes Serial thrombotic episodes

Chronic DICChronic DIC Laboratory abnormalitiesLaboratory abnormalities

Modestly increased prothrombin time in some patients Modestly increased prothrombin time in some patients Shortened or lengthened partial thromboplastin time Shortened or lengthened partial thromboplastin time Normal thrombin time in most patients Normal thrombin time in most patients High, normal, or low fibrinogen level High, normal, or low fibrinogen level High, normal, or low platelet count High, normal, or low platelet count Increased levels of FDP (eg, on testing for FDP, D Increased levels of FDP (eg, on testing for FDP, D

dimer) dimer) Evidence of molecular markers* (eg, thrombin-Evidence of molecular markers* (eg, thrombin-

antithrombin complexes, activation markers on antithrombin complexes, activation markers on platelet membranes, prothrombin fragment F1+2) platelet membranes, prothrombin fragment F1+2)

Current Management of Current Management of DICDIC

At present, diagnosis requires a set At present, diagnosis requires a set of blood tests; therapy focuses on of blood tests; therapy focuses on reversing the underlying disorder reversing the underlying disorder and providing supportive treatment. and providing supportive treatment.

Case 1 Presentation Case 1 Presentation A 56-year-old man was admitted to the A 56-year-old man was admitted to the

emergency department after a car accident. emergency department after a car accident.

•He had several bone fractures, a cerebral contusion, and He had several bone fractures, a cerebral contusion, and hemodynamic instability caused by a ruptured spleen. hemodynamic instability caused by a ruptured spleen. •Emergency splenectomy and aggressive administration of fluids Emergency splenectomy and aggressive administration of fluids restored hemodynamic stability, and the patient was transferred to restored hemodynamic stability, and the patient was transferred to the intensive care unit (ICU). the intensive care unit (ICU).

A few hours later, A few hours later, profuse extravasationprofuse extravasation was noted from was noted from the abdominal drains, the abdominal drains, endotracheal tube, endotracheal tube, and puncture sites of all intravascular linesand puncture sites of all intravascular lines..

Case 1 PresentationCase 1 Presentation

Laboratory tests showed a rapidly falling Laboratory tests showed a rapidly falling hemoglobin level and a platelet count of hemoglobin level and a platelet count of 25,000/µL. 25,000/µL.

The activated partial thromboplastin The activated partial thromboplastin time (aPTT) was 44 sec (normal, <28) time (aPTT) was 44 sec (normal, <28) and the prothrombin time (PT) was 29 and the prothrombin time (PT) was 29 sec (normal, <12.5). sec (normal, <12.5).

The level of fibrinogen degradation The level of fibrinogen degradation products was 360-520 g/L (normal, <40) products was 360-520 g/L (normal, <40) and the plasma antithrombin III level and the plasma antithrombin III level was 28% (normal, 80-120). was 28% (normal, 80-120).

Case 1 PresentationCase 1 Presentation Based on these findings, the diagnosis was DIC Based on these findings, the diagnosis was DIC

secondary to severe trauma. Surgical exploration secondary to severe trauma. Surgical exploration revealed diffuse oozing of blood at the site of the revealed diffuse oozing of blood at the site of the operation, but only partial surgical hemostasis operation, but only partial surgical hemostasis could be achieved. could be achieved.

The patient was given supportive treatment withThe patient was given supportive treatment with::

large infusions of fresh frozen plasma large infusions of fresh frozen plasma platelet concentrates. platelet concentrates.

The bleeding stopped 48 hours later. The bleeding stopped 48 hours later. Coagulation parameters eventually returned to Coagulation parameters eventually returned to normal and the subsequent clinical course was normal and the subsequent clinical course was uneventful. uneventful.

The pathogenesis of DIC The pathogenesis of DIC

Selected Disorders ThatSelected Disorders ThatMay Be Associated with DIC May Be Associated with DIC Malignancy (solid tumors, myeloproliferative, Malignancy (solid tumors, myeloproliferative,

lymphoproliferative) Obstetric emergencies lymphoproliferative) Obstetric emergencies (amniotic fluid embolism, abruptio placentae) (amniotic fluid embolism, abruptio placentae)

Organ destruction (severe pancreatitis) Organ destruction (severe pancreatitis) Sepsis/severe infection (any microorganism) Sepsis/severe infection (any microorganism) Severe hepatic failure Severe hepatic failure Severe toxic or immunologic reactions (snake Severe toxic or immunologic reactions (snake

bites, recreational drugs, transfusion reactions, bites, recreational drugs, transfusion reactions, transplant rejection) transplant rejection)

Trauma (polytrauma, neurotrauma, trauma Trauma (polytrauma, neurotrauma, trauma resulting in fat embolism) resulting in fat embolism)

Vascular abnormalities (Kasabach-Merritt Vascular abnormalities (Kasabach-Merritt syndrome, large vascular aneurysms)syndrome, large vascular aneurysms)

Infection.Infection. Bacterial infection, in particular septicemia, is Bacterial infection, in particular septicemia, is

commonly associated with DIC. However, commonly associated with DIC. However, systemic infections with other microorganisms, systemic infections with other microorganisms, such as viruses and parasites, also may lead to such as viruses and parasites, also may lead to DIC. DIC.

Components of the microorganism's cell Components of the microorganism's cell membrane (lipopolysaccharide, or membrane (lipopolysaccharide, or endotoxinendotoxin) or ) or bacterial exotoxins (e.g. bacterial exotoxins (e.g. staphylococcal alpha-staphylococcal alpha-toxintoxin) may cause a generalized inflammatory ) may cause a generalized inflammatory response characterized by systemic production of response characterized by systemic production of cytokines, mainly by activated mononuclear cells cytokines, mainly by activated mononuclear cells and endothelial cells. and endothelial cells.

The cytokines are responsible for the The cytokines are responsible for the derangement of the coagulation system in DIC. derangement of the coagulation system in DIC.

Trauma Trauma

Head trauma in particular is strongly Head trauma in particular is strongly associated with DIC; both local and associated with DIC; both local and systemic activation of coagulation may systemic activation of coagulation may be detected after such an event.be detected after such an event.

The increased risk of DIC after head The increased risk of DIC after head

trauma is understandable in view of trauma is understandable in view of the relatively large amount of the relatively large amount of tissue tissue factorfactor in the cerebral compartment. in the cerebral compartment.

Cancer Cancer Both solid tumors and hematologic Both solid tumors and hematologic

malignancies may be complicated by DIC. malignancies may be complicated by DIC. The mechanism by which the coagulation The mechanism by which the coagulation

system becomes deranged is poorly system becomes deranged is poorly understood. However, most studies implicate understood. However, most studies implicate tissue factortissue factor, perhaps expressed on the , perhaps expressed on the surface of tumor cells. surface of tumor cells.

A distinct form of DIC is frequently A distinct form of DIC is frequently encountered in patients with acute encountered in patients with acute promyelocytic leukemia; it is characterized by a promyelocytic leukemia; it is characterized by a severe severe hyperfibrinolysishyperfibrinolysis superimposed on an superimposed on an activated coagulation system.activated coagulation system.

Although clinical bleeding predominates in Although clinical bleeding predominates in such cases, disseminated thrombosis is found at such cases, disseminated thrombosis is found at autopsy in a considerable number of patients. autopsy in a considerable number of patients.

Obstetric Emergencies Obstetric Emergencies Acute DIC occurs in obstetric complications such as Acute DIC occurs in obstetric complications such as

amniotic fluid embolism and abruptio placentae. amniotic fluid embolism and abruptio placentae. Amniotic fluid can activate coagulation in vitroAmniotic fluid can activate coagulation in vitro, and , and

in abruptio placentae, the degree of placental separation in abruptio placentae, the degree of placental separation correlates with the severity of DIC, suggesting that correlates with the severity of DIC, suggesting that leakage of thromboplastinlike material from the leakage of thromboplastinlike material from the placental system triggers DIC in these patients. placental system triggers DIC in these patients.

The most common obstetric complication associated The most common obstetric complication associated with activation of coagulation is preeclampsia. Severe with activation of coagulation is preeclampsia. Severe preeclampsia may also be complicated by :preeclampsia may also be complicated by :

HELLP syndromeHELLP syndrome ( (hhemolysis, emolysis, eelevated levated liliver enzymes, ver enzymes, and and llow ow pplatelets). The latter, however, is characterized latelets). The latter, however, is characterized by a microangiopathic hemolytic anemia with secondary by a microangiopathic hemolytic anemia with secondary changes in the coagulation system. It is related to, but changes in the coagulation system. It is related to, but clearly distinct from, DIC. clearly distinct from, DIC.

Vascular Disorders Vascular Disorders Large aortic aneurysms or giant Large aortic aneurysms or giant

hemangiomas (Kasabach-Merritt syndrome) hemangiomas (Kasabach-Merritt syndrome) may result in local activation of coagulation may result in local activation of coagulation factors. factors.

The activated local factors can ultimately The activated local factors can ultimately overflow to the systemic circulation and overflow to the systemic circulation and cause DIC; more commonly, systemic cause DIC; more commonly, systemic depletion of coagulation factors and depletion of coagulation factors and platelets results from local consumption. platelets results from local consumption.

The ensuing clinical condition may be The ensuing clinical condition may be difficult to distinguish from DIC. difficult to distinguish from DIC.

Microangiopathic hemolytic Microangiopathic hemolytic anemia anemia

Microangiopathic hemolytic anemiaMicroangiopathic hemolytic anemia is a group of is a group of disorders that includes:disorders that includes:

thrombotic thrombocytopenic purpura, hemolytic uremic thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, chemotherapy-induced microangiopathic syndrome, chemotherapy-induced microangiopathic hemolytic anemia, malignant hypertension, and hemolytic anemia, malignant hypertension, and HELLP HELLP syndromesyndrome. .

A common pathogenetic feature appears to be endothelial A common pathogenetic feature appears to be endothelial damage, which promotes platelet adhesion and aggregation, damage, which promotes platelet adhesion and aggregation, thrombin formation, and impaired fibrinolysis. thrombin formation, and impaired fibrinolysis.

Although some characteristics of microangiopathic hemolytic Although some characteristics of microangiopathic hemolytic anemia and the resulting thrombotic occlusion of small and anemia and the resulting thrombotic occlusion of small and mid-size vessels (leading to organ failure) may mimic the mid-size vessels (leading to organ failure) may mimic the clinical presentation of DIC, these disorders in fact represent clinical presentation of DIC, these disorders in fact represent a distinct group of diseases. a distinct group of diseases.

Early events in sepsis Early events in sepsis 1) The intital toxic stimuli, such as endotoxin (LPS), triggers production of proinflammatory cytokines (TNF, IL-1) and monocyte adherence to endothelial cells.

2) TNF and IL-1 also activates neutrophils and endothelial cells for increased adherence. All activated cells release secondary inflammatory mediators, including cytokines.

3) Activation of platelets and increased production of procoagulants by endothelial cells may trigger microthrombosis. In some cases, disseminated intravascular coagulation (DIC) may occur with life-threatening tissue ischemia.

4) Vessel dilation caused by free radicals, histamine, prostaglandins, prostacyclin, and the kinin and tachykinin family of molecules, combined with the effects of cytokines on the endothelial cells, contribute to increased vascular permeability for fluids and low-molecular weight substances,

causing oedema. If the process is

wide-spread, a capillary leak syndrome may result.

Case 2 Presentation Case 2 Presentation A 71-year-old woman was admitted to the ICU A 71-year-old woman was admitted to the ICU

with sepsis complicated by hemodynamic and with sepsis complicated by hemodynamic and respiratory instability. respiratory instability.

Four days earlier, she had undergone a Four days earlier, she had undergone a duodenopancreatectomy for pancreatic carcinoma. duodenopancreatectomy for pancreatic carcinoma.

Fever, chills, and abdominal pain developed on the Fever, chills, and abdominal pain developed on the fourth day, and a computed tomographic scan fourth day, and a computed tomographic scan showed an intra-abdominal abscess. showed an intra-abdominal abscess.

The diagnosis was septic shock complicated by The diagnosis was septic shock complicated by respiratory failure, which was caused by adult respiratory failure, which was caused by adult respiratory distress syndrome. respiratory distress syndrome.

Case 2 PresentationCase 2 Presentation The patient was treated with intravenous fluids and The patient was treated with intravenous fluids and

vasopressors, intubation and mechanical ventilation, vasopressors, intubation and mechanical ventilation, surgical drainage of the abscess, and intravenous surgical drainage of the abscess, and intravenous antibiotics. antibiotics.

Acute renal failure and hepatic insufficiency Acute renal failure and hepatic insufficiency supervened during the next several days. Moreover, supervened during the next several days. Moreover, the patient's respiratory status deteriorated; the the patient's respiratory status deteriorated; the cause was determined to be a large pulmonary cause was determined to be a large pulmonary embolism. embolism.

Laboratory tests showed persistent Laboratory tests showed persistent thrombocytopenia (platelet count, 30,000-40,000/µL) thrombocytopenia (platelet count, 30,000-40,000/µL) and prolonged global clotting times: aPTT, 40-45 sec; and prolonged global clotting times: aPTT, 40-45 sec; PT, 20-25 sec. Fibrin degradation product levels PT, 20-25 sec. Fibrin degradation product levels were very high (>1600 µg/L; normal <40), and the were very high (>1600 µg/L; normal <40), and the antithrombin III level was 30%. antithrombin III level was 30%.

Case 2 PresentationCase 2 Presentation Based on those findings, DIC secondary to Based on those findings, DIC secondary to

sepsis was diagnosed. sepsis was diagnosed. The patient received supportive treatment The patient received supportive treatment

with intravenous with intravenous heparin and heparin and antithrombin IIIantithrombin III concentrate (50-70 U/kg), concentrate (50-70 U/kg), with a goal of producing greater than with a goal of producing greater than normal plasma concentrations. normal plasma concentrations.

After 10 days in the ICU, the patient After 10 days in the ICU, the patient gradually recovered and all organ function gradually recovered and all organ function normalized. One month after her operation, normalized. One month after her operation, she was discharged from the hospital in she was discharged from the hospital in good condition. good condition.

Diagnosis of DICDiagnosis of DIC

TestResult

Platelet count Markedly decreased

Prothrombin time Increased

Activated partial thromboplastin time Increased

Fibrin degradation products Markedly increased

Fibrinogen Normal or decreased

Antithrombin III Markedly decreased

Protein C Markedly decreased

Specific Therapies Specific Therapies

Platelet and Coagulation Factor Platelet and Coagulation Factor InfusionInfusion

HeparinHeparin

Platelet and Coagulation Platelet and Coagulation Factor InfusionFactor Infusion

Although low levels of platelets and coagulation factors Although low levels of platelets and coagulation factors may increase the risk of bleeding in patients with DIC, may increase the risk of bleeding in patients with DIC, plasma or platelet transfusions should not be given on plasma or platelet transfusions should not be given on the basis of laboratory test results alone; the basis of laboratory test results alone; they are they are indicated only in patients with active bleeding and in indicated only in patients with active bleeding and in those who require an invasive procedure or are those who require an invasive procedure or are otherwise at risk for bleedingotherwise at risk for bleeding. .

The suggestion that administration of blood The suggestion that administration of blood components might exacerbate DIC has never been components might exacerbate DIC has never been proved in clinical or experimental studies. The efficacy proved in clinical or experimental studies. The efficacy of treatment with plasma or platelets has not been of treatment with plasma or platelets has not been confirmed in randomized controlled trials; however, it confirmed in randomized controlled trials; however, it appears to be a rational therapy in patients who are appears to be a rational therapy in patients who are bleeding or at risk for bleeding because of significant bleeding or at risk for bleeding because of significant depletion of these elements. depletion of these elements.

Heparin Heparin Experimental studies have shown that Experimental studies have shown that heparin can at least heparin can at least

partly inhibit the activation of coagulation in DIC partly inhibit the activation of coagulation in DIC secondary to sepsis and other causessecondary to sepsis and other causes. .

In addition, patients with DIC need prophylaxis against In addition, patients with DIC need prophylaxis against venous thromboembolism. venous thromboembolism.

The benefit of heparin has been shown in a small, The benefit of heparin has been shown in a small, uncontrolled series of patients with DIC but has never uncontrolled series of patients with DIC but has never been demonstrated in controlled clinical trials. The safety been demonstrated in controlled clinical trials. The safety of heparin in patients with DIC who are prone to bleeding of heparin in patients with DIC who are prone to bleeding is often debated, but clinical studies have not shown that is often debated, but clinical studies have not shown that heparin significantly worsens bleeding complications in heparin significantly worsens bleeding complications in this group. this group.

Altogether, heparin is probably useful in Altogether, heparin is probably useful in patients with DIC, patients with DIC, particularly in thoseparticularly in those with clinically overt thromboembolism with clinically overt thromboembolism or extensive fibrin deposition, such as purpura fulminans or extensive fibrin deposition, such as purpura fulminans or ischemia in the extremities. or ischemia in the extremities.

Heparin is usually given in a relatively low-dose, Heparin is usually given in a relatively low-dose, continuous infusion (300-500 U/hr). continuous infusion (300-500 U/hr).

Recent studies show that low-molecular-weight heparin Recent studies show that low-molecular-weight heparin can be used as an alternative to unfractionated heparin. can be used as an alternative to unfractionated heparin.

Experimental Therapies Experimental Therapies

Theoretically, the most logical Theoretically, the most logical anticoagulation therapy in patients anticoagulation therapy in patients with DIC is an agent that is directed with DIC is an agent that is directed against tissue factor activity. against tissue factor activity.

Indeed, inhibitors of the tissue factor Indeed, inhibitors of the tissue factor pathway have been developed and pathway have been developed and ongoing clinical studies are ongoing clinical studies are evaluating their efficacy and safety evaluating their efficacy and safety in DIC. in DIC.

Experimental TherapiesExperimental Therapies Restoration of physiologic anticoagulation pathways Restoration of physiologic anticoagulation pathways

might be an appropriate therapeutic option in DIC. might be an appropriate therapeutic option in DIC. Antithrombin III is one of the most important natural Antithrombin III is one of the most important natural inhibitors of coagulation; patients with DIC almost inhibitors of coagulation; patients with DIC almost invariably have an acquired deficiency of the substance. invariably have an acquired deficiency of the substance.

Administration of supraphysiologic concentrations of Administration of supraphysiologic concentrations of antithrombin III has produced promising results in antithrombin III has produced promising results in clinical trials involving patients with sepsis or septic clinical trials involving patients with sepsis or septic shock, with or without DIC. Some trials showed a shock, with or without DIC. Some trials showed a modestly (but statistically insignificant) reduced mortality modestly (but statistically insignificant) reduced mortality in patients treated with antithrombin III. A metaanalysis in patients treated with antithrombin III. A metaanalysis of the trials showed that mortality decreased from 56% to of the trials showed that mortality decreased from 56% to 44% (odds ratio, 0.63; 95% confidence interval, 0.39 to 44% (odds ratio, 0.63; 95% confidence interval, 0.39 to 1.0). A large, randomized, controlled multicenter trial of 1.0). A large, randomized, controlled multicenter trial of supraphysiologic doses of antithrombin III in patients supraphysiologic doses of antithrombin III in patients with sepsis is currently under way, and its outcome will with sepsis is currently under way, and its outcome will more definitively determine the place of antithrombin III more definitively determine the place of antithrombin III treatment in sepsis and DIC. treatment in sepsis and DIC.

Experimental TherapiesExperimental Therapies

Another promising treatment is Another promising treatment is recombinant activated protein C. recombinant activated protein C.

This compound is now being evaluated in This compound is now being evaluated in large multicenter trials in patients with large multicenter trials in patients with sepsis, DIC, or both. In view of the pivotal sepsis, DIC, or both. In view of the pivotal role of protein C as inhibitor of the role of protein C as inhibitor of the coagulation cascade and its postulated role coagulation cascade and its postulated role as an important mediator of inflammation, as an important mediator of inflammation, activated protein C may be a good activated protein C may be a good candidate for supportive treatment of candidate for supportive treatment of patients with DIC. patients with DIC.

Treatment options for Treatment options for DIC DIC

Acute DICAcute DIC   Without bleeding or evidence of ischemia   Without bleeding or evidence of ischemia      No treatment      No treatment   With bleeding   With bleeding      Blood components as needed      Blood components as needed      Fresh frozen plasma      Fresh frozen plasma      Cryoprecipitate      Cryoprecipitate      Platelet transfusions      Platelet transfusions   With ischemia   With ischemia      Anticoagulants (see "with thromboembolism"       Anticoagulants (see "with thromboembolism" below) afterbelow) after      bleeding risk is corrected with blood products      bleeding risk is corrected with blood products

Treatment options for Treatment options for DICDIC

Chronic DICChronic DIC   Without thromboembolism   Without thromboembolism      No specific therapy needed but       No specific therapy needed but prophylactic drugsprophylactic drugs      (eg, low-dose heparin, low-molecular-      (eg, low-dose heparin, low-molecular-weight heparin)weight heparin)      may be used for patients at high risk of       may be used for patients at high risk of thrombosisthrombosis   With thromboembolism   With thromboembolism      Heparin or low-molecular-weight heparin,       Heparin or low-molecular-weight heparin, trial of warfarintrial of warfarin      sodium (Coumadin). (If warfarin is       sodium (Coumadin). (If warfarin is unsuccessful, long-term useunsuccessful, long-term use      of low-molecular-weight heparin may be       of low-molecular-weight heparin may be helpful.)* helpful.)*

DICDIC

DIC - Gangrene in patient with meningococcal sepsis

Schistocytes on the Peripheral Blood Smear

DICDIC

Subdermal bleeding at IV site following a bite by Hoplocephalus stephensi

Disseminated intravascular coagulation Disseminated intravascular coagulation (DIC).(DIC).

Patient with Postvaricella purpura fulminans showing extent of necrotic lesions Leg after skin grafting

14 year old otherwise healthy male who three weeks after primary varicella infection developed large painful lesions on his leg. (Fig 1). Laboratories evaluation showed evidence of disseminated intravascular coagulation (DIC). Plasma free protein S level was below 5% with other factors only mildly decreased (consistent with his DIC).

Patient was treated with heparin and plasma infusion which resulted in stabilization of his lesions. For his presumed autoimmune protein S deficiency he received immunoglobulin. Over the course of the next several months his protein S levels increased back into the normal range but his skin lesions required extensive grafting (fig 2 and 3).

The E N DThe E N D