Disseminated Intravascular
Coagulation
Nigel S. Key, MD
Professor
Division of Hematology/Oncology
What Is DIC?
DIC: Definition
An acquired syndrome characterized by the
intravascular activation of coagulation with
loss of localization arising from different
causes. It can originate from and cause
damage to the microvasculature, which if
sufficiently severe, can produce organ
dysfunction
Taylor, FB, et al. Thromb Haemost 2001;86:1327
Common Conditions Associated With
Disseminated Intravascular Coagulation
Infection (Sepsis syndromes (gram (+) and gram (-) bacteria), Viral
infections (e.g. Dengue, Ebola), Other (e.g. Ricketsial, Malarial
infections))
Trauma/Tissue Damage (Head injury, Pancreatitis, Fat embolism, Any
other serious tissue damage (crush or penetrating injury))
Malignancy (Solid tumors, Acute leukemias (especially AML-M3), Chronic
leukemias (CMML))
Obstetric Complications (Abruptio placentae, Amniotic fluid embolism)
Vascular Disorders (Giant hemangiomas (Kasabach-Merritt syndrome),
Other vascular malformations, Large aortic aneurysm)
Severe Allergic/Toxic Reactions (Toxic shock syndrome, Snake, spider
venoms)
Severe Immunologic Reactions (Acute hemolytic transfusion reactions,
Heparin-induced thrombocytopenia, type II))
Severe Sepsis: A Complex Clinical
Syndrome
Systemic
Inflammation
High mortality rate
(28%-50%)
Heterogeneous
patient population
Coagulation
Impaired
Fibrinolysis
Activation
Etiology of DIC in Sepsis
Zeerleder, S. et al. Chest 2005;128:2864-2875
Purpura Fulminans
apply.
Coagulation Activation via the TF Pathway
Zeerleder, S. et al. Chest 2005;128:2864-2875
Time-Dependent Increase in Monocyte-TF and PLT-TF
Procoagulant Activity After LPS Administration In Vivo
TF PCA (fold)
20
*
LPS
15
Mono TF PCA (pg/mL)
PLT TF PCA (pg/mL))
10
*
5
0
* vs
-1 2
0 hr, P <0.05 Time (hour)
24
Bach RR, Key NS, Jilma B
Role of Anticoagulation in DIC
No clear benefit of heparin
demonstrated in any of the handful of
RCTs, but
Consider for those patients with
o documented thromboembolic event
o acral ischemia
o purpura fulminans
Acute Promelocytic Leukemia
Maslak, P. ASH Image Bank 2004:101126
APL: Intracerebral Hemorrhage
DIC; Are We Dealing with
Apples and Oranges?
Mechanisms of Bleeding in DIC
1. Hyper-acute process leading to
uncompensated rapid consumption of
clotting factors and platelets (e.g.
Obstetric causes)
2. Hyper-fibrinolytic bleeding due to
ectopic production of plasminoegn
activators
Hyperfibrinolysis in APL (AML-M3)
Mennell J, et al. NEJM 1999;340:994-1004
Therapeutic Effects of ATRA in
AML-M3
Arbuthnot C & Wilde JT. Blood Rev 2006;20:289-297
Impact of ATRA on Early
Deaths in APL
Visani G, et al. Eur J Haematol 2000;64:139-144
Frequency of Bleeding in DIC Varies with
Cause and Presence of Hyperfibrinolysis
Okajima K, et al. Am J Hematol 2000;65:215-222
Role of Blood Products in DIC
No randomized trials; not even true
consensus guidelines
Do not use routine blood product
prophylaxis, but.
Consider blood products for those who
are actively bleeding or about to undergo
an invasive procedure. Goals:
platelets >50,000
fibrinogen > 1g/L
PT and aPTT as close to normal as possible
DIC: Phases
Overt DIC
Decompensated form
Non-overt DIC
More subtle hemostatic dysfunction
Taylor, FB, et al. Thromb Haemost 2001;86:1327
Defining DIC: Relevance
Pathogenesis: To define more completely the
sequence of events that determines the evolution
of biochemical or non-overt DIC to overt DIC
Prognostication: To propose targets, based on a
more complete understanding of the sequence
along this possible continuum, for possible
intervention to block progression to overt DIC
The Ideal Algorithm for the Diagnosis
of DIC
Simple Based primarily on clinical and global
tests of coagulation as well as a screening assay
for intravascular soluble fibrin formation
Practical Detailed understanding of hemostasis
biochemistry not required to use the diagnostic
paradigm
The Ideal Algorithm for the Diagnosis
of DIC
Flexible Diagnosis of DIC (whether overt or non-
overt) should be coupled with diagnosis and staging of
the underlying disorder based on clinical signs and
symptoms (e.g. SIRS)
Reliable The paradigm (particularly when used with
available molecular marker data) authenticates
appropriate and timely therapeutic intervention
Overt DIC Scoring System
Taylor, FB, et al. Thromb Haemost 2001;86:1327
The Conversion of Fibrinogen to FN
Nesheim, M. Chest 2003;124:33S-39S
Prospective Validation of the
.
ISTH Overt DIC Scoring System
N = 217
DIC Prevalence
= 32%
Bakhtiari K, et
al. Crit Care
Med 2004; 32:
2416-21
ISTH Non-Overt DIC Score
Emphasis on scoring for
abnormal trends, and inclusion
of molecular markers of
hemostasis
(protein C, AT levels) to
increase specificity.
Transition from adaptive to
maladaptive responses.
Non-Overt DIC Score
Taylor, FB, et al. Thromb Haemost 2001;86:1327
Validation of the ISTH Non-Overt DIC
Score:Consecutive ICU Admissions
Identical 28-Day Mortality for Patients
with Overt and Non-Overt DIC
Toh CH and Downey C. Blood Coag and Fibrinol 2005;16:69-74
Non Overt DIC score = 90/450 (20%)
Overt DIC score 5 = 49/450 (11%)
Non
Overt
DIC
74
55
78%
16
15
33
23
78%
Overt
DIC
Prognostic Impact of
DIC in Sepsis
Coagulation as an important denominator of outcome in
sepsis.
NEJM 1999; 341: 586
DIC
independent predictor of
mortality in sepsis & trauma.Chest 1992; 101: 8
reversing cause does not always ameliorate DIC.
BMJ 2003; 327: 974
Activated Protein C Improves
Survival in Severe Sepsis (The
PROWESS Trial)
Bernard, GR, et al. NEJM 2001;344:699-709
ISTH Overt DIC Score: an Important
Predictor of 28-day Mortality in
Severe Sepsis in the PROWESS Study*
Odds
Ratio
Per unit of
overt
DIC score**
Per
APACHE II
point
Per year
of age
1.29***
1.07***
1.03***
*Post hoc analysis
**29% (454/1568) had overt DIC at study entry
***p<0.001
Dhainaut J-F, et al. J Thromb Haemost 2006;2:1924-1933
Effect of rhAPC on Mortality
by Baseline Overt DIC Status
Overt DIC at
Baseline?
(n)
rhAPC:
n/mortality
Placebo:
n/mortality
Relative
Risk
(95% CI)
No
(1114)
567/22.1% 547/27.1%
0.81
(0.66-1.00)
Yes
(454)
233/30.5% 221/43.0%
0.71
(0.55-0.91)
Dhainaut J-F, et al. J Thromb Haemost 2006;2:1924-1933
Interpretation
The ISTH overt DIC scoring
system may identify severe
sepsis patients at high risk of
death, with a favorable
response profile to rhAPC??
The KyberCept (High Dose Antithrombin in
Sepsis) Trial : 90 Day Survival Rates
Increased bleeding
risk in those who
received heparin+AT
(not shown)
Primary Outcome
*p = 03
Post Hoc Analysis
Warren, B. L. et al. JAMA
2001;286:1869-1878.
Influence of DIC (Overt or Non-Overt) on AT
Responsiveness in Sepsis (Kybercept Trial)
Post-hoc analysis of 563 patients not receiving heparin.
Baseline Prevalence of DIC = 41% (Overt 8%; Non-overt 39%; Both 6%)
*
*p = 0.015
QuickTime and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
Kienast, J et al. J Thromb Haemost 2006;4:90
Interpretation
High dose AT without
concomitant heparin in septic
patients with DIC may result
in a significant mortality
reduction??
Conclusions
The ISTH Overt DIC and Non-overt DIC scoring
systems provide a new framework for the diagnosis and
severity scoring of DIC
These templates have been prospectively validated in
independent patient populations (both as a tool to define
diagnostic scores for DIC, and as a method to demonstrate
prognostic associations for overt and non-overt DIC with
mortality risk)
These scoring systems offer new opportunities for
objective assessment of therapeutic interventions in DIC
As yet, it is unclear how well the scoring systems
perform for all forms of DIC
