1. DISSEMINATED INTRAVASCULAR COAGULATION

2. SOLUBLE FIBRIN IN DIC →Non-adherent/soluble fibrin, no platelets
MONKEY (E. COLI INJECTION)
HUMAN (ACUTE LEUKEMIA)
→Non-adherent/soluble fibrin, no platelets

3. CAUSES OF DIC Blood exposed to excess tissue factor Endothelial damage
Tissue factor expression by monocytes
Massive tissue/organ injury
Cancer
Obstetric catastrophe
Activation of fibrinolysis
Secondary to thrombin formation (t-PA)
Cancer/leukemia (t-PA, u-PA, other)
Cardiopulmonary bypass
Other procoagulant or profibrinolytic substances
Cancer cells
Venoms

4. VASCULAR SUBENDOTHELIUM AND CIRCULATING MONOCYTES ARE POTENTIAL SOURCES OF TISSUE FACTOR
Am J Pathol 1989; 134:
LARGE VESSEL
MONOCYTE
MONOCYTE + ENDOTOXIN
SMALL VESSEL

5. INFLAMMATORY CYTOKINES INDUCE GAPS IN ENDOTHELIAL MONOLAYER
J Exp Med 1989;169:
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

6. BACTERIAL LIPOPOLYSACCHARIDE INDUCES TISSUE FACTOR mRNA EXPRESSION IN HEALTHY VOLUNTEERS
Thrombin
Franco et al, Blood 2000;96:554-9

7. Cancer cells shed tissue factor-rich membrane vesicles
Fibrin deposits around tumor cells
Intravascular fibrin
Dvorak et al, 1981

8. LEUKEMIC CELLS EXPRESS A VARIETY OF PROCOAGULANT AND PROFIBRINOLYTIC SUBSTANCES
Tissue factor
Urokinase
tPA
Elastase
Cytokines
Annexin II

9. INFLAMMATION AND LIVER DISEASE PROMOTE DIC
Inflammation (TNF, IL-1, IL-6, etc)
Upregulation of procoagulant pathways
Downregulation of profibrinolytic pathways
Effects on endothelium
Increased risk of tissue damage/organ failure
Liver disease
Inhibitor deficiency (antithrombin, antiplasmin, protein C, etc)
Diminished clotting factor production
Delayed clearance of FDP
Increases severity of DIC, may increase bleeding risk

10. ANTI PRO Normal PRO A tipped scale An unstable balance Inflammation
Liver disease
A tipped scale
An unstable balance

11. Bacterial lipopolysaccharide (LPS) induces fibrin deposition in rat kidney more efficiently than tissue factor (TF)
Asakura et al, Crit Care Med 2002;30:161

12. TNF levels correlate strongly with mortality in children with infectious purpura fulminans
100 80
Under 0.15 60
Mortality (%) 40
Over 1.00 20
TNF level (ng/ml)
NEJM 1988;319:

13. COMPLICATIONS OF DIC
Bleeding
Thrombosis
Tissue necrosis

14. CAUSES OF BLEEDING IN DIC
Clotting factor consumption
High levels of FDP (inhibit fibrin formation)
Endothelial damage
Increased fibrinolytic activity

15. FIBRINOLYSIS Plasminogen Plasmin PAI-1 TPA UK PI PI Fibrin FDP
Platelets
Fibroblasts
Macrophage
Endothelial cell
Plasminogen
Plasmin
PAI-1
TPA UK
Liver 2 PI 2 PI
Fibrin
FDP
Fibrinogen
Fibrin catalyzes its own destruction
Depletion of platelets & antiplasmin increases systemic fibrinolysis

16. Bleeding severity correlates with low antiplasmin activity
100 80 60
0-2+ bleeding
% of patients
3-4+ bleeding 40 20
< 50%
50-75%
> 75%
Antiplasmin activity
Arch Intern Med 1989;149:1769

17. DIC WITH HYPERFIBRINOLYSIS
Examples
Acute leukemia (particularly promyelocytic)
Metastatic cancer (esp. prostate)
Cardiopulmonary bypass
Liver disease or transplantation

18. THROMBOSIS IN DIC Large vessel thrombosis uncommon
Disordered clotting
Increased fibrinolysis
More common in "chronic DIC"
e.g., Trousseau syndrome
Clots may form around intravascular catheters, etc

19. TISSUE INJURY IN DIC: PUPURA FULMINANS
High level bacteremia
NEJM 2004;351:2636
NEJM 2001;344:1593
Pneumococcal sepsis in a splenectomized patient

20. PURPURA FULMINANS IN MENINGOCOCCEMIA
High level bacteremia
Blood 2005;105:11
NEJM 2001;344:1372

21. PURPURA FULMINANS IS OFTEN ASSOCIATED WITH MULTIPLE ORGAN FAILURE
ADRENAL GLAND
(Waterhouse-Friderichsen syndrome)
NEJM 2005;353:1245
RENAL CORTEX
Hum Pathol 1972;3:327

22. TISSUE NECROSIS AND DIC (PURPURA FULMINANS)
Contributing factors
Intravascular fibrin
Endothelial damage
Downregulated fibrinolysis
Hypotension
Pressor administration
Acquired protein C deficiency

23. PROTEIN C 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

24. ACTIVATED PROTEIN C HAS ANTICOAGULANT AND CYTOPROTECTIVE EFFECTS
Blood 2007; 109:3161

25. HOMOZYGOUS PROTEIN C DEFICIENCY WITH NEONATAL PURPURA FULMINANS

26. WARFARIN-INDUCED SKIN NECROSIS IN A PROTEIN C-DEFICIENT PATIENT

27. PURPURA FULMINANS IN A PATIENT WITH AN ACQUIRED INHIBITOR OF APC

28. PROTEIN C IN BACTERIAL SEPSIS
Baboon model
With normally lethal dose of E. coli:
Activated protein C prevents DIC, tissue necrosis and death
Another 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
F.B. Taylor et al, J Clin Invest 1987; Blood 1991; Blood 2000

29. Protein C levels predict ICU survival as well as the APACHE II or SAPS II score
Anesthesiology 2007;107:15

30. DIC PATHOPHYSIOLOGY Summary 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

31. DIAGNOSIS OF DIC DIC is likely when there is:
A condition known to cause DIC
Evidence of accelerated fibrinolysis and clotting factor consumption

32. LABORATORY TESTS IN DIC
GUIDE TREATMENT
DIAGNOSIS
FDP or D-Dimer
PT/INR
Fibrinogen
Fibrinogen
PT/INR
Platelet count
Platelet count
Alpha2-antiplasmin
Fibrin monomer

33. Death Is
Coming

34. SEVERE DIC IS ASSOCIATED WITH A HIGH MORTALITY RATE
Thromb Haemost 1980; 43:28-33
346 patients with overt DIC
77% bled excessively
68% died
72% with bleeding
63% without bleeding
Most deaths from underlying disease, not bleeding

35. TREATMENT OF DIC TREAT UNDERLYING DISEASE!
Clotting factor & inhibitor replacement
Fresh frozen plasma
Cryoprecipitate
Platelets
Antithrombin III concentrate?
Activated protein C concentrate
Pharmacologic inhibitors
Heparin
Antifibrinolytics

36. REPLACEMENT THERAPY IN DIC
Product
Content
Indication
Risk
All clotting factors and inhibitors
Volume
virus transmission
FFP
INR > 1.6
Fibrinogen, VIII, VWF
Fibrinogen <
Cryoprecipitate
"Feed the fire"?
Platelets
Platelets < 30-50K
Purified antithrombin
Antithrombin ? ?
Severe sepsis
Purpura fulminans?
Activated protein C*
Recombinant APC
Bleeding
*Withdrawn from market

37. IS THERE A ROLE FOR ANTICOAGULANT OR 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

38. HEPARIN IN DIC Rationale: Indications: Risks:
Prevent thrombin/fibrin formation
and secondary fibrinolysis
Indications:
Cancer-associated DIC
Acute leukemia and DIC
Chronic DIC with aneurysm, etc
Overt 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

39. ANTIFIBRINOLYTIC DRUGS
Lysine analogs block binding of tPA and plasminogen to lysine residues on fibrin

40. ANTIFIBRINOLYTIC THERAPY IN DIC
Rationale:
Inhibit activation of plasminogen/clot lysis
Prevent bleeding
Indications:
DIC in promyelocytic leukemia
DIC 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

41. COMBINED ANTICOAGULANT AND ANTIFIBRINOLYTIC TREATMENT OF DIC ASSOCIATED WITH PROSTATE CARCINOMA
60 yo man post XRT for spine mets with diffuse bleeding

42. PROTEIN C REPLACEMENT IN PURPURA FULMINANS
A prospective, open-label clinical trial
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 % range
Two patients also received antithrombin concentrate
OUTCOME
OBSERVED
PREDICTED
Death 8%
50%
Amputation
12%
30%
Blood 2000;96:3719

43. RECOMBINANT ACTIVATED PROTEIN C INFUSION IN SEVERE SEPSIS
NEJM 2001;344:699
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

44. Effects of rAPC infusion on survival and D-dimer levels in patients with severe sepsis
NEJM 2001;344:699