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Disseminated IntravascularCoagulationNigel S. Key, MD

ProfessorDivision of Hematology/Oncology

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What Is DIC?

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DIC: Definition

An acquired syndrome characterized by theintravascular activation of coagulation with

loss of localization arising from differentcauses. It can originate from and cause

damage to the microvasculature, which if

sufficiently severe, can produce organdysfunction

Taylor, FB, et al. Thromb Haemost 2001;86:1327

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Common Conditions Associated With

Disseminated Intravascular CoagulationInfection (Sepsis syndromes (gram (+) and gram (-) bacteria), Viralinfections (e.g. Dengue, Ebola), Other (e.g. Ricketsial, Malarialinfections))

Trauma/Tissue Damage(Head injury, Pancreatitis, Fat embolism, Anyother 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))

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Severe Sepsis: A Complex ClinicalSyndrome

High mortality rate

(28%-50%) Heterogeneous

patient population

SystemicInflammation

ImpairedFibrinolysis

Coagulation

Activation

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Zeerleder, S. et al. Chest 2005;128:2864-2875

Etiology of DIC in Sepsis

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Purpura Fulminans

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Zeerleder, S. et al. Chest 2005;128:2864-2875

Coagulation Activation via the TF Pathway

Ti D d t I i M t TF d PLT TF

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0

5

10

15

20

TF

PCA

(fold)

-1 2 4 6 8 24

Time (hour)

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

LPS

*

*vs 0 hr, P

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Role of Anticoagulation in DIC No clear benefit of heparindemonstrated in any of the handful of

RCTs, but

Consider for those patients witho documented thromboembolic evento acral ischemia

o purpura fulminans

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Maslak, P. ASH Image Bank 2004:101126

Acute Promelocytic Leukemia

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APL: Intracerebral Hemorrhage

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DIC; Are We Dealing with

Apples and Oranges?

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Mechanisms of Bleeding in DIC1. Hyper-acuteprocess leading to

uncompensated rapid consumption ofclotting factors and platelets (e.g.

Obstetric causes)2. Hyper-fibrinolyticbleeding due to

ectopic production of plasminoegn

activators

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Hyperfibrinolysis in APL (AML-M3)

Mennell J, et al. NEJM1999;340:994-1004

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Therapeutic Effects of ATRA inAML-M3

Arbuthnot C & Wilde JT. Blood Rev2006;20:289-297

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Impact of ATRA on Early

Deaths in APL

Visani G, et al. Eur J Haematol2000;64:139-144

f l d h

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Frequency of Bleeding in DIC Varies withCause and Presence of Hyperfibrinolysis

Okajima K, et al. Am J Hematol2000;65:215-222

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Role of Blood Products in DIC No randomized trials; not even true

consensus guidelines Do not use routineblood product

prophylaxis, but.

Consider blood products for those whoare actively bleeding or about to undergoan invasive procedure. Goals: platelets >50,000 fibrinogen > 1g/L PT and aPTT as close to normal as possible

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DIC: PhasesOvert DIC

Decompensated form

Non-overt DIC More subtle hemostatic dysfunction

Taylor, FB, et al. Thromb Haemost 2001;86:1327

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Defining DIC: Relevance

Pathogenesis: To define more completely thesequence of events that determines the evolution

of biochemical or non-overt DIC to overt DIC

Prognostication: To propose targets, based on amore complete understanding of the sequence

along this possible continuum, for possibleintervention to block progression to overt DIC

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The Ideal Algorithm for the Diagnosisof DIC

Simple Based primarily on clinical and globaltests of coagulation as well as a screening assay

for intravascular soluble fibrin formation

PracticalDetailed understanding of hemostasisbiochemistry not required to use the diagnostic

paradigm

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The Ideal Algorithm for the Diagnosis

of DIC

FlexibleDiagnosis of DIC (whether overt or non-overt) should be coupled with diagnosis and staging of

the underlying disorder based on clinical signs andsymptoms (e.g. SIRS)

Reliable The paradigm (particularly when used with

available molecular marker data) authenticatesappropriate and timely therapeutic intervention

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Overt DIC Scoring System

Taylor, FB, et al. Thromb Haemost 2001;86:1327

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Nesheim, M. Chest 2003;124:33S-39S

The Conversion of Fibrinogen to FN

P ti V lid ti f th

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Bakhtiari K, et

al. Crit CareMed2004; 32:2416-21

.

Prospective Validation of theISTH Overt DIC Scoring System

N = 217

DIC Prevalence= 32%

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ISTH Non-Overt DIC Score

Transition from adaptive tomaladaptive responses.

Emphasis on scoring for

abnormal trends, and inclusion

of molecular markers ofhemostasis

(protein C, AT levels) to

increase specificity.

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Non-Overt DIC ScoreTaylor, FB, et al. Thromb Haemost 2001;86:1327

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Validation of the ISTH Non-Overt DICScore:Consecutive ICU Admissions

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Identical 28-Day Mortality for Patientswith Overt and Non-Overt DIC

Non Overt DIC score = 90/450 (20%)Overt DIC score 5 = 49/450 (11%)

55

15

23

78%

78%

74 16 33NonOvert

DICOvert

DIC

Toh CH and Downey C. Blood Coag and Fibrinol 2005;16:69-74

P ti I t f

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Coagulation as an important denominator of outcome insepsis.

NEJM1999; 341: 586 DIC

independent predictor ofmortality in sepsis & trauma.Chest1992; 101: 8

reversing cause does not always ameliorate DIC. BMJ2003; 327: 974

Prognostic Impact of

DIC in Sepsis

A ti t d P t i C I

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Activated Protein C ImprovesSurvival in Severe Sepsis (The

PROWESS Trial)

Bernard, GR, et al. NEJM 2001;344:699-709

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ISTH O t DIC S I t t

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ISTH Overt DIC Score: an ImportantPredictor of 28-day Mortality in

Severe Sepsis in the PROWESS Study*

Per unit ofovert

DIC score**

Per

APACHE II

point

Per yearof age

OddsRatio 1.29*** 1.07*** 1.03***

*Post hoc analysis**29% (454/1568) had overt DIC at study entry***p

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Effect of rhAPC on Mortalityby Baseline Overt DIC StatusOvert DIC at

Baseline?

(n)

rhAPC:

n/mortality

Placebo:

n/mortality

RelativeRisk

(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

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Interpretation

The ISTH overt DIC scoringsystem may identify severe

sepsis patients at high risk of

death, with a favorableresponse profile to rhAPC??

The KyberCept (High Dose Antithrombin in

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Warren, B. L. et al. JAMA2001;286:1869-1878.

The KyberCept (High Dose Antithrombin inSepsis) Trial : 90 Day Survival Rates

*p = 03*

Primary Outcome

Post Hoc Analysis

Increased bleedingrisk in those whoreceived heparin+AT

(not shown)

Influence of DIC (Overt or Non Overt) on AT

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Influence of DIC (Overt or Non-Overt) on ATResponsiveness in Sepsis (Kybercept Trial)

QuickTime and a

TIFF (Uncompressed) decompressorare needed to see this picture.

Kienast, J et al. J Thromb Haemost 2006;4:90

*

*p = 0.015

Post-hoc analysis of 563 patients notreceiving heparin.

Baseline Prevalence of DIC = 41% (Overt 8%; Non-overt 39%; Both 6%)

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Interpretation

High dose ATwithoutconcomitant heparinin septicpatients with DICmay result

in a significant mortalityreduction??

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ConclusionsThe ISTH Overt DIC and Non-overt DIC scoringsystems provide a new framework for the diagnosis andseverity scoring of DIC

These templates have been prospectively validated inindependent patient populations (both as a tool to definediagnostic scores for DIC, and as a method to demonstrateprognostic associations for overt and non-overt DIC with

mortality risk) These scoring systems offer new opportunities forobjective assessment of therapeutic interventions in DIC

As yet, it is unclear how well the scoring systems

f f ll f f D