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