Diagnosis and treatment of disseminated
intravascular coagulation (DIC)
Marcel Levi, MD
Academic Medical Center
University of Amsterdam
the Netherlands
Coagulation abnormalities
in 350 consecutive ICU patients
surgical
cardio
Thrombocytopenia
in critically ill patients
Vanderschueren S, Crit Care Med 2000; 28(6):1871-1876.
Bleeding as a cause of death in
thrombocytopenia
60
m o rta lity (% )
50
40
fatal nonbleeding
platelet count is
independent
predictor of
mortality
30
20
10
fatal
bleeding
0
0
platelet count <100
is associated with
2-fold increased
mortality
<20
20-60
60-100
>100
mortality is only
partly dependent of
bleeding
Causes of thrombocytopenia in the ICU
8%
44%
10%
5%
2%
1%
8%
22%
Levi et al., Crit Care Med 2005
sepsis + DIC
sepsis - DIC
various DIC
viral infection
TTP/HUS
bleeding/transfusion
HIT
various
The spectrum of coagulopathy in
systemic inflammatory states
Sensitive
molecular
markers
Laboratory
abnormalities
Disseminated
intravascular
coagulation
DIC
disseminated intravascular coagulation
consumption coagulopathy
systemic intravascular fibrin formation
consumptive defibrination
systemic thrombohemorraghic syndrome
...
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)
N Engl J Med 1955
The clinical picture of DIC
systemic activation of coagulation
intravascular
fibrin deposition
organ failure
consumption of
platelets and
coagulation factors
bleeding
Evidence for involvement of microvascular
thrombosis in the pathogenesis of DIC
1.
ischemia and necrosis due to fibrin
deposition in (micro)vasculature in
DIC patients
2.
experimental studies: amelioration
of coagulation abnormalities
improves organ function and
reduces mortality
3.
DIC is an independent predictor of
mortality in clinical studies
Levi et al, Blood 2003
Evidence for involvement of microvascular
thrombosis in the pathogenesis of DIC
120
100
DIC is an independent
80
60
DIC
non DIC
predictor of mortality
40
in 10 clinical studies
20
in patients with sepsis
0
Inflammatory activation and
microvascular thrombosis contribute to
multiple organ failure
Wheeler and Bernard, NEJM 2005
endotoxin
cytokines
coagulation activation
endotoxin
mononuclear cell
tissue
factor
cytokines
coagulation activation
mononuclear cells
express tissue factor in
septic patients
meningococcemia
monocytes express
tissue factor mRNA
upon endotoxin in vivo
125-fold increase in tissue
factor expression on monocytes
inflammation
coagulation
inflammation
coagulation
Levi et al., Circulation 2006
Levi et al., Circulation 2006
Levi et al., Circulation 2006
Crit Care Med 2008
coagulation
coagulation
inflammation
the diagnosis
the clinical
picture of DIC
systemic activation of coagulation
intravascular
fibrin deposition
organ failure
consumption of
platelets and
coagulation factors
bleeding
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 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 III and/or protein C
elevated fibrin split products, FDP’s, D-dimer, etc.
concensual DIC score (SSC/ISTH)
platelet count
•
•
<100
<50
0-2
:
:
1
2
D-dimer
•
•
ULN-5xULN
> 5 x ULN
0-3
:
:
2
3
prolonged PT
•
•
< 3 sec
> 3 sec
low fibrinogen
Thromb Haemostas 2001
0-2
:
:
1
2
0-1
> 5: “DIC”
30
mortality overt DIC
sensitivity score: 91%
43%
25
20
specificity score: 97%
15
mortality
no DIC
positive
predictive
value: 95%
10
27% predictive value: 96%
negative
5
0
0
1
2
3
4
5
6
>7
reduction in mortality
reduction in coagulation activation
(and inflammatory mediators?)
less organ failure
rh-APC
mortality
DIC
30%
Placebo
mortality
43%
RR
38%
(95% CI 9–45)
No DIC
22%
27%
19%
(95% CI 0–34)
Ely W., et al.,
Crit Care 2003
overt DIC
no DIC
antithrombin
placebo
DIC
• similar trend for
antithrombin treatment
(subgroup analysis
Kybersept trial)
• needs prospective
validation
No DIC
predictive value of the DIC score
with and without fibrinogen
91
98
90
97
agreement without
fibrinogen
agreement with
fibrinogen
disagreement with
fibrinogen
disagreement without
fibrinogen
9
score <5
10
2
score>5
3
Point of care testing
• Helpful in identifying
platelet, coagulation
and fibrinolytic
defects
• Not validated for
hypercoagulability
• No clinical
(management) studies
in DIC
NEW POINTS OF IMPACT WITH DIAGNOSTIC
AND THERAPEUTIC RELEVANCE
TTP
HUS
Malignant
hypertension
Sepsis
mechanical
cytokine-induced
primary
verotoxin-induced
ADAMTS13 endothelial damage endothelial damage endothelial damage
deficiency (secondary low levels of (secondary low levels of (secondary low levels of
ADAMTS-13)
ADAMTS-13)
ADAMTS-13)
ultra-large von Willebrand factor multimers
increased platelet-vessel wall interaction
microthrombosis
hemolysis
organ failure
(kidney, brain, etc.)
New targets?
downregulation of thrombomodulin in sepsis
Faust et al., NEJM 2001
New targets?
Glycocalyx: a new player in DIC pathogenesis?
dramatic loss of glycocalyx volume in DIC
2.00
1.75
135
130
*
125
120
1.25
115
*
110
Hyaluronan (ng/ml)
Systemic glycocalyx volume (liters)
1.50
1.00
0.75
0.50
105
*
100
95
*
90
85
80
75
70
0.25
65
60
0.00
Glyc Norm I
healthy
Glyc Norm II
Glyc HG
Glyc MAN
Type of intervention
control
hyperglycemia DIC
55
0
2
4
6
8
10
Time (hours)
12
14
16
20 25 30
Loss of glycocalyx in sepsis results in
activation of coagulation
2.25
1.1
*
2.00
1.0
0.9
1.75
*
0.8
1.50
*
*
0.7
1.25
D-dimer
(g/L)
prothombin fragments 1+2
(nmol/L)
*
*
1.00
0.6
0.5
0.4
0.75
0.3
0.50
0.2
0.25
0.1
0.00
0
1
2
3
4
Time (hours)
5
6
7
0.0
0
1
2
3
4
Time (hours)
5
6
7
Conclusion
DIC is a consequence of a simultaneous systemic activation
of inflammatory and coagulation systems
The diagnosis of DIC is mostly indirect and employs
routine coagulation parameters and a composite scoring
system
In patients with DIC the scoring system allows:
• acceptable accuracy in the diagnosis of DIC
• powerful prognostic value
• selection of patients that may need specialized/expensive
treatment
New insights in the pathogenesis of DIC may yield
new diagnostic and therapeutic options
acknowledgement
Anne Cornelie de Pont
Joost Meijers
Harry Buller
Tom van der Poll

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Dr Polly LEUNG