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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