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

Coagulation
Activation

High mortality rate (28%-50%) Heterogeneous patient population

Impaired Fibrinolysis

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

20 TF PCA (fold) 15 10

*
LPS

*
Mono TF PCA (pg/mL) PLT TF PCA (pg/mL))

* 5 0

-1 2

24
Bach RR, Key NS, Jilma B

* vs

0 hr, P <0.05 Time (hour)

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

biochemistry not required to use the diagnostic paradigm

Practical Detailed understanding of hemostasis

The Ideal Algorithm for the Diagnosis of DIC

overt) should be coupled with diagnosis and staging of the underlying disorder based on clinical signs and symptoms (e.g. SIRS)

Flexible Diagnosis of DIC (whether overt or non-

available molecular marker data) authenticates appropriate and timely therapeutic intervention

Reliable The paradigm (particularly when used with

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*
Per unit of overt DIC score** Odds Ratio 1.29*** Per APACHE II point 1.07*** Per year of age

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) 0.81 (0.66-1.00) 0.71 (0.55-0.91)

No (1114) Yes (454)

567/22.1% 547/27.1%

233/30.5% 221/43.0%

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

Primary Outcome

Increased bleeding risk in those who received heparin+AT (not shown)

*
Post Hoc Analysis

*p = 03

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