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ISTH Advanced Training CourseDubai, UAE

ISTH Advanced Training Course

Disseminated Intravascular coagulation

December 2, 2016


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

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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)


DIC disseminated intravascular coagulation

consumption coagulopathy

systemic intravascular fibrin formation

consumptive defibrination

systemic thrombohemorraghic syndrome

...

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the clinical picture of DICsystemic activation of coagulation

intravascular consumption of

fibrin deposition platelets and

coagulation factors

organ failure bleeding


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


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


N Engl J Med 1955


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


Sensitive Laboratory Disseminatedmolecular abnormalities intravascularmarkers coagulation

the spectrum of coagulopathy in systemic inflammatory states


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

Wheeler and Bernard, NEJM 1999


lipopolysaccharides

cytokines

coagulation activation

mononuclear cell


lipopolysaccharides

cytokines


mononuclear cell

?


lipopolysaccharides

cytokines


mononuclear cell

tissue factor


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


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


inflammation

coagulation


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, UAECoughlin, J Clin Invest 2003


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


antithrombin antithrombin levels are low (<30-50%)

in severe inflammatory states• consumption• impaired synthesis• degradation

low levels are correlated with higher mortality


Faust et al., NEJM 2001

downregulation of thrombomodulin in sepsis


coagulation


coagulation

inflammation


Pathogenetic pathways in DICcytokines

tissue factor-mediated dysfunctional impairedthrombin anticoagulant fibrinolysis

generation mechanisms due to PAI-1

fibrin inadequateformation fibrin removal

fibrin deposition


Pathogenetic pathways in DICcytokines

tissue factor-mediated dysfunctional impairedthrombin anticoagulant fibrinolysis

generation mechanisms due to PAI-1

fibrin inadequate formation fibrin removal

fibrin deposition


fibrinolytic response in DIC

PAI-1t-PA

plasmin


Bridging theory to practice

management of DIC

pathogenesis





coagulation factors






coagulation factors


the diagnosis of DIC


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


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, FDP’s, D-dimer, etc.


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

• <100 : 1• <50 : 2

D-dimer 0-3• ULN-5xULN : 2• > 5 x ULN : 3

prolonged PT 0-2• < 3 sec : 1• > 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%


predictive value of the DIC scorewith and without fibrinogen

9097

92

103

9891

score <5 score>5

agreement withoutfibrinogenagreement withfibrinogendisagreement withfibrinogendisagreement withoutfibrinogen


Point of care testing

• Helpful in identifying platelet, coagulation and fibrinolytic defects

• Not validated for hypercoagulability

• No clinical (management) studies in DIC


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


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* -0.071, -0.002 No

Levi et al., Am J Resp Crit Care Med 2007

• RR = 0.89 (0.77-0.99)


subgroup: patients already on heparin

0.5 0.6 0.7 0.8 1 1.25 1.67 20.9Relative Risk of Death (Point Estimate and 95% CI)

Overall

Baseline heparin-Yes

Baseline heparin - No

Breslow-Day p = 0.03

heparin placebo

myocardial infarction

3/455 6/455ischemic stroke

5/455 17/455DVT/PE 2/455 5/455


reduction in mortality

reduction in coagulation activation (and inflammatorymediators)

less organ failure

APCmortality

Placebo mortality

RRR

DIC 30% 43% 38%(95% CI 9–45)

No DIC 22% 27% 19%(95% CI 0–34)


• similar trend for antithrombin treatment (subgroup analysis Kybersept trial)

• needs prospective validation

antithrombin

placebo

DIC

No DIC


Randomizedn=750

Placebon=370

Treatedn=741

ART-123n=371

Death (74)Lost to follow-up (2)

Withdrew consent (3)

Death (63)Lost to follow-up (1)

Withdrew consent (2)

Completed studyn=305

Did not complete study

n=66

Completed studyn=292

Did not complete study

n=79

Critical Care Med 2013


conclusion pathogenesis (and clinical relevance) of DIC has

become increasingly clear

endothelial cells and mononuclear cells play a pivotal role at the crossroad of inflammation and coagulation; considerable cross-talk between coagulation and inflammation

increased knowledge may lead to better management modalities for DIC

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