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ISTH Advanced Training CourseDubai, UAE

ISTH Advanced Training Course

Disseminated Intravascular coagulation

December 2, 2016

ISTH Advanced Training CourseDubai, UAE

Disclosures for In compliance with COI policy, ISTH requires the following disclosures to the session audience:

Research Support/P.I. Johnson&Johnson, Sanquin

Employee No relevant conflicts of interest to declare

Consultant No relevant conflicts of interest to declare

Major Stockholder No relevant conflicts of interest to declare

Speakers Bureau No relevant conflicts of interest to declare

Honoraria No relevant conflicts of interest to declare

Scientific Advisory Board Asahi Kasei, Novo Nordisk, Pfizer

- 2 -

ISTH Advanced Training CourseDubai, UAE

DIC hemorrhois defibrination

after snake bite (A.E. Celcus, CE 170)

injection of brain material into animals results in widespread clot formation and death(Dupuy, Gaz Med Paris,1834)

ISTH Advanced Training CourseDubai, UAE

DIC disseminated intravascular coagulation

consumption coagulopathy

systemic intravascular fibrin formation

consumptive defibrination

systemic thrombohemorraghic syndrome

...

- 4 -

ISTH Advanced Training CourseDubai, UAE

the clinical picture of DICsystemic activation of coagulation

intravascular consumption of

fibrin deposition platelets and

coagulation factors

organ failure bleeding

ISTH Advanced Training CourseDubai, UAE

Evidence for involvement of microvascular thrombosis in the pathogenesis of DIC

1. ischemia and necrosis due tofibrin deposition in (micro)vasculature in DIC patients

2. experimental studies: amelioration of coagulation abnormalities improves organfunction and reduces mortality

3. DIC is an independent predictor of mortality in clinical studies

Levi et al, Blood 2003

ISTH Advanced Training CourseDubai, UAE

microvascular thrombosis in the pathogenesis of DIC

0

20

40

60

80

100

120

DICnon DIC

DIC is anindependent predictor of mortality in 10 clinical studies in patients withsepsisLevi M, et al. N Engl J Med 2011

ISTH Advanced Training CourseDubai, UAE

N Engl J Med 1955

ISTH Advanced Training CourseDubai, UAE

most important clinical conditionsthat may be complicated by DIC sepsis

trauma

malignancy solid tumors

hematological malignancies

obstetrical calamities

vascular abnormalities aneurysms

giant hemangioma

severe allergic/toxic reactions

ISTH Advanced Training CourseDubai, UAE

ISTH Advanced Training CourseDubai, UAE

Sensitive Laboratory Disseminatedmolecular abnormalities intravascularmarkers coagulation

the spectrum of coagulopathy in systemic inflammatory states

ISTH Advanced Training CourseDubai, UAE

inflammatory activation and microvascular thrombosis contribute to multiple organ failure in DIC

Wheeler and Bernard, NEJM 1999

ISTH Advanced Training CourseDubai, UAE

ISTH Advanced Training CourseDubai, UAE

lipopolysaccharides

cytokines

coagulation activation

mononuclear cell

ISTH Advanced Training CourseDubai, UAE

lipopolysaccharides

cytokines

coagulation activation

mononuclear cell

?

ISTH Advanced Training CourseDubai, UAE

lipopolysaccharides

cytokines

coagulation activation

mononuclear cell

tissue factor

ISTH Advanced Training CourseDubai, UAE

monocytes express tissue factor mRNA

upon endotoxin in vivo

125-fold increase in tissue factor expression

Franco et al, Blood 2000

mononuclear cells express tissue factor

in septic patients

Levi et al, Blood 1995

meningococcemia

ISTH Advanced Training CourseDubai, UAE

control anti- tissue factor

kidney

liver

0

5

10

15

20

25

30

35

40

t=12 t=24

anti-TF

control

anti-tissue factor

in septic baboons

survival

Levi, Blood 2005

ISTH Advanced Training CourseDubai, UAE

inflammation

coagulation

ISTH Advanced Training CourseDubai, UAE

wt PSLG -/- p-selectin -/-

platelets

tissue factor

fibrin J Exp Med 2003

P-selectin from platelets induce tissue factor expression on mononuclear cells

ISTH Advanced Training CourseDubai, UAELevi et al., Circulation 2006

ISTH Advanced Training CourseDubai, UAELevi et al., Circulation 2006

ISTH Advanced Training CourseDubai, UAELevi et al., Circulation 2006

ISTH Advanced Training CourseDubai, UAECoughlin, J Clin Invest 2003

ISTH Advanced Training CourseDubai, UAE

tissue factor +factor VII(a)

factor Xa(+ factor Va)

factor IXa(+ factor VIIIa)

factor IIa(thrombin)

factor XIa

fibrinogen fibrin

antithrombin

TFPI

protein C system

Natural inhibitors of coagulation

ISTH Advanced Training CourseDubai, UAE

antithrombin antithrombin levels are low (

ISTH Advanced Training CourseDubai, UAE

ISTH Advanced Training CourseDubai, UAE

Faust et al., NEJM 2001

downregulation of thrombomodulin in sepsis

ISTH Advanced Training CourseDubai, UAE

ISTH Advanced Training CourseDubai, UAE

coagulation

ISTH Advanced Training CourseDubai, UAE

coagulation

inflammation

ISTH Advanced Training CourseDubai, UAE

Pathogenetic pathways in DICcytokines

tissue factor-mediated dysfunctional impairedthrombin anticoagulant fibrinolysis

generation mechanisms due to PAI-1

fibrin inadequateformation fibrin removal

fibrin deposition

ISTH Advanced Training CourseDubai, UAE

Pathogenetic pathways in DICcytokines

tissue factor-mediated dysfunctional impairedthrombin anticoagulant fibrinolysis

generation mechanisms due to PAI-1

fibrin inadequate formation fibrin removal

fibrin deposition

ISTH Advanced Training CourseDubai, UAE

fibrinolytic response in DIC

PAI-1t-PA

plasmin

ISTH Advanced Training CourseDubai, UAE

Bridging theory to practice

management of DIC

pathogenesis

ISTH Advanced Training CourseDubai, UAE

the clinical picture of DICsystemic activation of coagulation

intravascular consumption of

fibrin deposition platelets and

coagulation factors

organ failure bleeding

ISTH Advanced Training CourseDubai, UAE

the clinical picture of DICsystemic activation of coagulation

intravascular consumption of

fibrin deposition platelets and

coagulation factors

organ failure bleeding

the diagnosis of DIC

ISTH Advanced Training CourseDubai, UAE

Diagnosis of DIC detection of soluble fibrin

measurement of fibrin monomers

markers of thrombin generation

limitations: reasonable sensitivity but limited specificity large variation between tests not (yet) available in routine setting

ISTH Advanced Training CourseDubai, UAE

diagnosis DIC in routine setting

platelet count (low and/or dropping)

prolongation of global clotting tests (PT, aPTT)

optionally: low levels of coagulation factors(also to exclude other coagulation defects)

low antithrombin and/or protein C

elevated fibrin split products, FDPs, D-dimer, etc.

ISTH Advanced Training CourseDubai, UAE

concensual DIC score (SSC/ISTH) platelet count 0-2

3 sec : 2

> 5: DIC Thromb Haemostas 2001

0

5

10

15

20

25

30

0 1 2 3 4 5 6 >7

sensitivity score: 91%specificity score: 97%positive predictive value: 95%negative predictive value: 96%

mortality overt DIC 43%

mortality no DIC 27%

ISTH Advanced Training CourseDubai, UAE

predictive value of the DIC scorewith and without fibrinogen

9097

92

103

9891

score 5

agreement withoutfibrinogenagreement withfibrinogendisagreement withfibrinogendisagreement withoutfibrinogen

ISTH Advanced Training CourseDubai, UAE

Point of care testing

Helpful in identifying platelet, coagulation and fibrinolytic defects

Not validated for hypercoagulability

No clinical (management) studies in DIC

ISTH Advanced Training CourseDubai, UAE

evidence for efficacy and safetyof heparin in DIC

uncontrolled case series and meta-analyses of clinical series: some success

efficacy not been demonstrated in randomizedcontrolled clinical trials

clinical studies: safety seems not to be a majorissue

ISTH Advanced Training CourseDubai, UAE

International, multi-center, randomized, double-blind, placebo-controlled study

Patients with Severe Sepsis Who Were UndergoingTreatment with Drotrecogin randomized for: unfractionated heparin LMW heparin placebo

Primary objective: 28-day all-cause mortality

Equivalence Analysis of 28-Day Mortality

Heparin PlaceboAbsolute

Risk 6.2%Died (%) Died (%) Difference 95% CI Equiv

275/972 28.3 305/955 31.9 -0.036* -

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