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Disseminated Intravascular
oagu a on
Dept of Internal Medicine Univ. of Indonesia
/Cipto Mangunkusumo Hospital
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• onsump ve coagu a on
• Defibrin(ogen)ation syndrome
• Thrombohemorrhagic syndrome
•
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epen s upon e :
• Triggering event (s)• Host response (s)
• Comorbid conditions
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CAUSES OF DIC
Infection ‐ bacterial sepsis, viral infections
Neo lasm ‐ AML, adenocarcinoma
Obstetrical disorders ‐ retained dead fetus, abruption, etc
‐ ra n n ury, crus , urns, e c.
Others ‐ acute hemolytic transfusion reaction
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Pathophysiology of Severe SepsisPathophysiology of Severe Sepsis
Endothelium COAGULATION
IL-6IL-1
PAI-1Factor VIIIa
Tissue Factor
Monocyte
TNF-
Suppressed
Factor Va
Bacteria
Neutrophil
TAFITHROMBIN
Fibrin
LPS / endotoxin
IL-6
Fibrin clotTissue Factor
to Infection
to Infection
to Infection
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Patho enesis of DIC
Release ofthromboplastic
material intocirculation
Consumption of coagulation factors;
presence of FDPs
Fibrinogen
Thrombin Plasmin
aPTT
PT
TT↓
Fibrin
↓
Presence of plasmin
FDP
Fibrin(ogen)Degradation
ProductsIntravascular clot
↓ Platelets
Clot
(intravascular) Plasmin
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Underlying disorder
Systemic activation o coagu ation
Widespread
intravascular fibrin
Consumption of
platelets and
(severe) Bleeding
organ failure
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Activation of coagulation
Events leading to
thrombosis
Events leading to
bleeding
Circulating thrombi
Thrombotic occlusion
of microcirculation of
all organs
Fibrinolysis
in the
microcirculation
Circulating fibrin
degradation
products
Consumption of
platelets and
coagulation proteins
+
Signs of microvascular thrombosis Signs of hemorrhagic diathesis
•Neuologic : multifocal, delirium, coma•Skin : focal ischemia, superficial gangrene
•Renal : oliguria, azotemia, cortical necrosis
•Pulmonary: acute respiratory distress syndrome
•
•Neuologic : intracerebral bleeding•Skin : petechiae, ecchymoses, venipuncture
oozing
•Renal : hematuria
• •Fragmentation hemolytic anemia
,
•GI: massive bleeding
Marder VJ. Hemost and Thromb. 5edt. 2006.1571‐1600
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CLINICAL PHASES OF DIC
c va on o e coagu a on
Preci itation of soluble fibrin with
consumption of coagulation factors
c va on an or n on o r no ys s
with microthrombosis, embolism and
emorr age
End‐or an failure and hemorrha eIV
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v ence o procoagu a on
• Elevated prothrombin fragment 1+2• Elevated fibrinopeptide A
• Elevated fibrinopeptide B
• ‐
• Elevated D‐dimer
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‐
• Elevated FDP
• Elevated plasmin
• Elevated plasmin antiplasmin complex
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• ‐
• Decreased alpha‐2‐antiplasmin
• Decrease eparin co actor II
• Decreased protein C or S• Elevated TAT complex
•
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‐
•
• Elevated creatinine
• Decrease pH
• Decreased paO2
Needs 2 out of 4 above items for diagnosis
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Features Affected Patients
•
• Renal dysfunction 25%
• Hepatic ys unction 19%
• Respiratory dysfunction 16%• Shock 14%
•
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Platelet count ↓
sMF (soluble fibrin
aPTT ↑
D‐dimer ↑ TT ↑
FDP (fibrin degradation
product) ↑
antithrombin ↓
National consensus of DIC in sepsis 2001
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Taylor, FB, et al. Thromb Haemost 2001;86:1327
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Vitamin K deficiency
Liver disease
Thrombotic thromboc to enic ur ura
Congenital abnormalities of fibrinogen
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Treat the underlying disease
Restore the circulation Re lacement thera
Cryoprecipitate/FFP
Packed red cells
controversial or investigational agents
, , , ,
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Treatment of acute, severe DIC (1)ModalityModality RationaleRationale DetailsDetails ExpectationsExpectations
Life supportLife support Self Self--evidentevident Fluids, blood, respiratoryFluids, blood, respiratory Maintain cardiac output, gasMaintain cardiac output, gas
measuresmeasures care,care, etcetc exchange, electrolyteexchange, electrolyte
balance, etcbalance, etc
Treating theTreating the Correct theCorrect the Dependent on theDependent on the Inhibit or block theInhibit or block the
un er y ngun er y ng
disorder disorder
cause ocause o pr mary agnos spr mary agnos s comp ca ng pa o og ccomp ca ng pa o og c
mechanism of DICmechanism of DIC inparallelinparallel
with the response (if any) ofwith the response (if any) of
the disorder the disorder
Antithrombotic Antithrombotic
agentsagents
BlockBlock
microthrombusmicrothrombus
formationformation
Heparin by continuous IVHeparin by continuous IV
infusion, monitor withinfusion, monitor with
fibrinogen and plateletfibrinogen and platelet
levels; continue as longlevels; continue as long
Prevent fibrin formation; tipPrevent fibrin formation; tip
the balance within thethe balance within the
microcirculation towardmicrocirculation toward
physiologicphysiologic fibrinolysisfibrinolysis; allow; allow
as the predisposingas the predisposingclinical state persists; ATclinical state persists; AT
III concentrate if AT IIIIII concentrate if AT III
level < 70%level < 70%
reperfusion of the skin,reperfusion of the skin,kidneys, and brainkidneys, and brain
Marder VJ. Hemost and Thromb. 5edt. 2006.1571‐1600
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Treatment of acute, severe DIC (2)
Modality Rationale Details Expectations
Tranfusion Reestablish normal
hemostastic potential
Infuse platelets and
fibrinogen
Platelet count and
fibrinogen should increase
(cryoprecipitate); repeat
as indicated bylaboratory and clinical
observation
significantly; bleeding
should diminish and stopduring an interval of hours
to several days
Transfusion
+ heparin
Restore normal
hemostasis if
transfusion of
hemostasis factors
Infuse platelets and
cryoprecipitate 2 h after
starting continous
heparin infusion (7.5
Platelet count and and
fibrinogen should increase
significantly if consumption
is blocked; bleeding should
fails to achieve
significant increment in
factor levels
U/kg/h); repeat as
indicated by laboratory
and clinical observation
diminish; if bleeding
increases, discontinue
heparin
Fibrinolytic Block excessive For adults ε- Bleeding ceases rapidly but
inhibitors fibrinolysis and theaccumulation of
degradation products
in blood; protect
aminocaproic acid;loading dose, 46 g, then
1 g q12h for a limited
duration (up to 48 h)
keeps vascular channelsoccluded with thrombus;
dangerous if the thrombotic
process was not previously
hemostatic plugs treated with heparin
Marder VJ. Hemost and Thromb. 5edt. 2006.1571‐1600
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Disorder Treatment approach
Purpura fulminants Heparin by continous infusion
cra or erma sc em a epar n y cont nous n us on
Venous thromboembolism Heparin by continous infusion
Bacteremia (associated with Heparin by continous infusion
dermal ischemia or necrosis)
Organ ischemia Heparin not indicated unless there is evidence or fibrin
deposition elsewhere (dermal or acral ischemia)
Retained dead fetus syndrome Heparin IV or cryoprecipitate alone if labor in progress
Giant hemangioma Thrombose with EACA and possibly cryoprecipitate;
before elective surgery, heparin, cryoprecipitate (or
both), and platelets
Aorta aneurysm without Heparin preceding elective repair
ruptureSolid tumors Heparin by continous infusion; if effective, then
adjusted‐dose or low‐molecular weight heparin s.c.
Promyelotic leukemia Acute promyelocytic leukemia
Marder VJ. Hemost and Thromb. 5edt. 2006.1571‐1600
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Disorder Treatment approach
Relative contraindication
Aortic aneurysm, leaking Cryoprecipitate and platelets preceding emergency repair
Hemorrhage in a closed spase
compromising vital function
Heparin a possible option but only with external drainage
Septicemia Heparin only with specific indications; high doses; high
oses o - concen ra e - eve
Abruptio placentae without significantbleeding
Blood volume replacement, prompt delivery, cryoprecipitateif needed
hemostatic factors if bleeding is present
Saline-induced abortion Correct excessive bleeding during delivery by replacing
fibrinogen and platelets
Septic abortion Consider heparin therapy early in course when DIC is
present
Severe liver disease with refractory Discontinue shunt
Acute fatty liver of pregnancy AT-III replacement, preferably by concentrate
Intracranial gunshot wound or severe
brain in ur
Cryoprecipitate and platelets
Marder VJ. Hemost and Thromb. 5edt. 2006.1571‐1600
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Anticoa ulation TheraRationale :
1. Septic process reveals with coagulationabnormality DIC.
2. Antithrombin, protein C, protein S and
tissue factor athwa inhibitor TFPI werenatural anticoagulant found to be reduced
‐. ,
indicate that coagulation pathway were
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The Role of Activated Protein C in Severe SepsisThe Role of Activated Protein C in Severe Sepsis
Endothelium Activated Protein CActivated Protein C
COAGULATION
IL-6IL-1
Inactivation n
PAI-1Factor VIIIaTissue Factor
Monocyte
TNF-
Inactivation
Inactivation
e v e n
t i o n
o f a c t i v a t i
SuppressedActivated h i b i t i o n
Factor Va
Neutrophil
P
TAFI
Protein C I n
n
THROMBIN
Fibrin
IL-6
I n h i b
i t i o
Activated Protein CFibrin clot
Tissue Factor
to Infection
to Infection
to Infection
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The evidence concernin use of rhAPC in adults is
primarily based on two RCTs:
• PROWESS (1,690 adult patients, stopped early forefficacy)
• s oppe ear y or u y
• Additional safety information comes from an open‐ , .
trial also suggested that early administration ofrhAPC was associated with better outcomes.
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PROWESS Survival Rates
RRR: 19.4% (95% CI 6.6 ‐ 30.5)
ARR: 6.1% => NNT=17
N Engl J Med. 2001; 344: 699‐709
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The KyberCept (High Dose Antithrombin in Sepsis)
Trial : 90 Da Survival Rates
Primary Outcome
Increased bleeding
risk in those whoreceived heparin+AT
(not shown)
*p = 03
Post Hoc Analysis
Warren, B. L. et al. JAMA
2001;286:1869‐1878.
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• DIC is a syndrome characterized systemic
intravascular coagulation.•
of intravascular thrombosis has the greatest
im act on morbidit and mortalit .
• The treatment of DIC is reversal or control of
,
and replacement therapy as indicated.
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an you