DISSEMINATED INTRAVASCULAR DISSEMINATED INTRAVASCULAR COAGULATIONCOAGULATION

SOLUBLE FIBRIN IN DICSOLUBLE FIBRIN IN DIC

MONKEY (E. COLI INJECTION) HUMAN (ACUTE LEUKEMIA)

→Non-adherent/soluble fibrin, no platelets

• Blood exposed to excess tissue factor Endothelial damageTissue factor expression by monocytesMassive tissue/organ injuryCancerObstetric catastrophe

• Activation of fibrinolysisSecondary to thrombin formation (t-PA)Cancer/leukemia (t-PA, u-PA, other)Cardiopulmonary bypass

• Other procoagulant or profibrinolytic substancesCancer cellsVenoms

CAUSES OF DICCAUSES OF DIC

VASCULAR SUBENDOTHELIUM AND VASCULAR SUBENDOTHELIUM AND CIRCULATING MONOCYTES ARE POTENTIAL CIRCULATING MONOCYTES ARE POTENTIAL

SOURCES OF TISSUE FACTORSOURCES OF TISSUE FACTOR

LARGE VESSEL MONOCYTEMONOCYTE

+ ENDOTOXIN

SMALL VESSEL

Am J Pathol 1989; 134:1087-97

INFLAMMATORY CYTOKINES INDUCE GAPS IN INFLAMMATORY CYTOKINES INDUCE GAPS IN ENDOTHELIAL MONOLAYERENDOTHELIAL MONOLAYER

J Exp Med 1989;169:1977-91

Control 5 nM TNF x 90 min 5 nM TNF x 24h

Cytokine-induced endothelial damage in the microcirculation exposes blood to a large pool of subendothelial tissue factor

BACTERIAL LIPOPOLYSACCHARIDE INDUCES TISSUE BACTERIAL LIPOPOLYSACCHARIDE INDUCES TISSUE FACTOR mRNA EXPRESSION IN HEALTHY VOLUNTEERSFACTOR mRNA EXPRESSION IN HEALTHY VOLUNTEERS

Franco et al, Blood 2000;96:554-9

Tissue factor mRNA Thrombin

Dvorak et al, 1981

Cancer cells shed tissue factor-rich membrane Cancer cells shed tissue factor-rich membrane vesiclesvesicles

Fibrin deposits around tumor cells

Intravascular fibrin

LEUKEMIC CELLS EXPRESS A VARIETY OF LEUKEMIC CELLS EXPRESS A VARIETY OF PROCOAGULANT AND PROFIBRINOLYTIC PROCOAGULANT AND PROFIBRINOLYTIC

SUBSTANCESSUBSTANCES

Tissue factor

Urokinase

tPA

ElastaseCytokines

Annexin II

• Inflammation (TNF, IL-1, IL-6, etc) Upregulation of procoagulant pathways Downregulation of profibrinolytic pathways Effects on endotheliumIncreased risk of tissue damage/organ failure

• Liver disease Inhibitor deficiency (antithrombin,

antiplasmin, protein C, etc) Diminished clotting factor production Delayed clearance of FDPIncreases severity of DIC, may increase

bleeding risk

INFLAMMATION AND LIVER DISEASE PROMOTE DICINFLAMMATION AND LIVER DISEASE PROMOTE DIC

ANTIPRO

ANTI

PRO

ANTIPRO

Normal

Inflammation Liver disease

A tipped scale An unstable balance

Bacterial lipopolysaccharide (LPS) induces fibrin deposition in rat Bacterial lipopolysaccharide (LPS) induces fibrin deposition in rat kidney more efficiently than tissue factor (TF)kidney more efficiently than tissue factor (TF)

Asakura et al, Crit Care Med 2002;30:161

TNF levels correlate strongly with mortality in TNF levels correlate strongly with mortality in children with infectious purpura fulminanschildren with infectious purpura fulminans

NEJM 1988;319:397-400

TNF level (ng/ml)0

20

40

60

80

100

Mor

talit

y (%

)

Under 0.15

0.15-0.50

0.50-1.00

Over 1.00

•Bleeding

•Thrombosis

•Tissue necrosis

COMPLICATIONS OF DICCOMPLICATIONS OF DIC

• Clotting factor consumption

• High levels of FDP (inhibit fibrin formation)

• Endothelial damage

• Increased fibrinolytic activity

CAUSES OF BLEEDING IN DICCAUSES OF BLEEDING IN DIC

FIBRINOLYSISFIBRINOLYSIS

Plasminogen

Plasmin

TPA UK

Fibrin FDP Fibrinogen

2PI 2PI

Fibroblasts

Macrophage

Liver

Platelets

Fibrin catalyzes its own destruction

PAI-1

Endothelial cell

Depletion of platelets & antiplasmin increases systemic fibrinolysis

Bleeding severity correlates with low antiplasmin activityBleeding severity correlates with low antiplasmin activity

< 50% 50-75% > 75%Antiplasmin activity

0

20

40

60

80

100

% o

f pat

ient

s

0-2+ bleeding

3-4+ bleeding

Arch Intern Med 1989;149:1769

• Acute leukemia (particularly promyelocytic)• Metastatic cancer (esp. prostate)• Cardiopulmonary bypass• Liver disease or transplantation

DIC WITH HYPERFIBRINOLYSISDIC WITH HYPERFIBRINOLYSISExamples

• Large vessel thrombosis uncommon Disordered clotting Increased fibrinolysis

• More common in "chronic DIC" e.g., Trousseau syndrome

• Clots may form around intravascular catheters, etc

THROMBOSIS IN DICTHROMBOSIS IN DIC

TISSUE INJURY IN DIC:TISSUE INJURY IN DIC:PUPURA FULMINANSPUPURA FULMINANS

Pneumococcal sepsis in a splenectomized patient

NEJM 2001;344:1593

High level bacteremia

NEJM 2004;351:2636

PURPURA FULMINANS IN MENINGOCOCCEMIAPURPURA FULMINANS IN MENINGOCOCCEMIA

NEJM 2001;344:1372

Blood 2005;105:11

High level bacteremia

ADRENAL GLAND(Waterhouse-Friderichsen syndrome)

NEJM 2005;353:1245

RENAL CORTEX

PURPURA FULMINANS IS OFTEN ASSOCIATED PURPURA FULMINANS IS OFTEN ASSOCIATED WITH MULTIPLE ORGAN FAILUREWITH MULTIPLE ORGAN FAILURE

Hum Pathol 1972;3:327

• Intravascular fibrin• Endothelial damage• Downregulated fibrinolysis• Hypotension• Pressor administration• Acquired protein C deficiency

TISSUE NECROSIS AND DICTISSUE NECROSIS AND DIC(PURPURA FULMINANS)(PURPURA FULMINANS)

Contributing factorsContributing factors

• Physiologic anticoagulant Vitamin K-dependent Destroys factors Va, VIIIa (Protein S is cofactor)

• Activated by thrombin bound to endothelium Activation downregulated by inflammatory cytokines

• Protective effect on endothelium Protein C receptor on endothelial cells Activated protein C modulates endothelial response to

inflammation and hypoxia

Severe deficiency of protein C can cause tissue necrosis

PROTEIN CPROTEIN C

ACTIVATED PROTEIN C HAS ANTICOAGULANT ACTIVATED PROTEIN C HAS ANTICOAGULANT AND CYTOPROTECTIVE EFFECTSAND CYTOPROTECTIVE EFFECTS

Blood 2007; 109:3161

HOMOZYGOUS PROTEIN C DEFICIENCY WITH HOMOZYGOUS PROTEIN C DEFICIENCY WITH NEONATAL PURPURA FULMINANSNEONATAL PURPURA FULMINANS

WARFARIN-INDUCED SKIN NECROSIS IN WARFARIN-INDUCED SKIN NECROSIS IN A PROTEIN C-DEFICIENT PATIENTA PROTEIN C-DEFICIENT PATIENT

PURPURA FULMINANS IN A PATIENT WITH PURPURA FULMINANS IN A PATIENT WITH AN ACQUIRED INHIBITOR OF APCAN ACQUIRED INHIBITOR OF APC

With normally lethal dose of E. coli:Activated protein C prevents DIC, tissue

necrosis and deathAnother inhibitor of thrombin formation blocks

DIC but not tissue necrosis and death

With normally sublethal dose of E. coli:Monoclonal antibodies to either protein C or its

endothelial receptor promote DIC, tissue necrosis and death

PROTEIN C IN BACTERIAL SEPSISPROTEIN C IN BACTERIAL SEPSISBaboon model

F.B. Taylor et al, J Clin Invest 1987; Blood 1991; Blood 2000

Protein C levels predict ICU survival as well as the Protein C levels predict ICU survival as well as the APACHE II or SAPS II scoreAPACHE II or SAPS II score

Anesthesiology 2007;107:15

• Excess tissue factor + flowing blood = DIC• Inflammatory cytokines set the stage for DIC and

contribute to tissue damage• Excessive fibrinolysis associated with higher

bleeding risk• Acquired protein C deficiency associated with high

risk of tissue necrosis/purpura fulminans

DIC PATHOPHYSIOLOGYDIC PATHOPHYSIOLOGYSummary

DIC is likely when there is:

1. A condition known to cause DIC2. Evidence of accelerated fibrinolysis and

clotting factor consumption

DIAGNOSIS OF DICDIAGNOSIS OF DIC

LABORATORY TESTS IN DICLABORATORY TESTS IN DIC

DIAGNOSISDIAGNOSIS GUIDE GUIDE TREATMENTTREATMENT

FDP or D-Dimer PT/INR

Fibrinogen Fibrinogen

PT/INR Platelet count

Platelet count Alpha2-antiplasmin

Fibrin monomer

DDeatheath

IIss

CComingoming

SEVERE DIC IS ASSOCIATED WITH A HIGH SEVERE DIC IS ASSOCIATED WITH A HIGH MORTALITY RATEMORTALITY RATE

• 346 patients with overt DIC• 77% bled excessively• 68% died

– 72% with bleeding– 63% without bleeding

Most deaths from underlying disease, not bleeding

Thromb Haemost 1980; 43:28-33

TREATMENT OF DICTREATMENT OF DIC• TREAT UNDERLYING DISEASE!

• Clotting factor & inhibitor replacementFresh frozen plasmaCryoprecipitatePlateletsAntithrombin III concentrate?Activated protein C concentrate

• Pharmacologic inhibitorsHeparin Antifibrinolytics

REPLACEMENT THERAPY IN DICREPLACEMENT THERAPY IN DIC

Product Content Indication Risk

FFP All clotting factors and inhibitors INR > 1.6 Volume

virus transmission

Cryoprecipitate Fibrinogen, VIII, VWF Fibrinogen < 50-100 "Feed the fire"?

Platelets Platelets < 30-50K

Antithrombin Purified antithrombin ? ?

Activated protein C* Recombinant APC Severe sepsisPurpura fulminans? Bleeding

*Withdrawn from market - 2011

IS THERE A ROLE FOR ANTICOAGULANT OR IS THERE A ROLE FOR ANTICOAGULANT OR ANTIFIBRINOLYTIC DRUGS IN DIC?ANTIFIBRINOLYTIC DRUGS IN DIC?

• No controlled trials have shown any benefit• Anecdotal evidence suggests these drugs

may help selected patients• Consider using such treatment in patients

with life-threatening bleeding that persists despite aggressive replacement therapy

HEPARIN IN DICHEPARIN IN DICRationale: Prevent thrombin/fibrin formation

and secondary fibrinolysis

Indications: Cancer-associated DICAcute leukemia and DICChronic DIC with aneurysm, etcOvert thrombosis (full dose heparin)Adjunct to antifibrinolytic Rx

Risks: Exacerbate bleeding (unlikely w/low dose)

Low dose (eg, 500 U/hr) of unfractionated heparin usually adequate

ANTIFIBRINOLYTIC DRUGS

Lysine analogs block binding of tPA and plasminogen to lysine residues on fibrin

ANTIFIBRINOLYTIC THERAPY IN DICANTIFIBRINOLYTIC THERAPY IN DIC

Rationale: Inhibit activation of plasminogen/clot lysisPrevent bleeding

Indications: DIC in promyelocytic leukemiaDIC with severe bleeding, low antiplasmin

Risk: Thrombosis uncommon (give w/heparin)Blanket contraindication in DIC unjustified

Amicar, 1 gram/hour i.v. with low dose heparin

COMBINED ANTICOAGULANT AND ANTIFIBRINOLYTIC COMBINED ANTICOAGULANT AND ANTIFIBRINOLYTIC TREATMENT OF DIC ASSOCIATED WITH PROSTATE CARCINOMATREATMENT OF DIC ASSOCIATED WITH PROSTATE CARCINOMA

60 yo man post XRT for spine mets with diffuse bleeding60 yo man post XRT for spine mets with diffuse bleeding

1 2 3 4 5 6 7 8DAY

0

50

100

150

200

250

300

Fibr

inog

en, m

g /dl

0

50

100

150

200

250

Platelets

• Subjects: 36 patients with meningococcemia, shock and purpura fulminans Mean age = 12 (3 months-72 yrs) Mean protein C activity 18%

• Intervention: Protein C concentrate, 100 IU/kg loading dose and 10 IU/kg/hr, adjusted to keep protein C activity in 80-120% range Two patients also received antithrombin concentrate

PROTEIN C REPLACEMENT IN PURPURA PROTEIN C REPLACEMENT IN PURPURA FULMINANSFULMINANS

A prospective, open-label clinical trialA prospective, open-label clinical trial

Blood 2000;96:3719

OUTCOME OBSERVED PREDICTED

Death 8% 50%

Amputation 12% 30%

• Subjects: 1690 patients with severe sepsis• Method: randomized, double-blind, placebo-

controlled multicenter trial• Intervention: rAPC infusion vs placebo• Outcomes:

Mortality lower in treated pts (24.7% vs 30.8%, p=.005)Serious bleeding more common in treated pts (3.5% vs

2%, p=.06)Subgroup analysis suggests greatest benefit in patients

with more severe sepsis & DIC

RECOMBINANT ACTIVATED PROTEIN C RECOMBINANT ACTIVATED PROTEIN C INFUSION IN SEVERE SEPSISINFUSION IN SEVERE SEPSIS

NEJM 2001;344:699

Effects of rAPC infusion on survival and D-dimer Effects of rAPC infusion on survival and D-dimer levels in patients with severe sepsislevels in patients with severe sepsis

NEJM 2001;344:699

Survival D-dimer