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DISSEMINATED INTRAVASCULAR COAGULATION

DISSEMINATED INTRAVASCULAR COAGULATION. MONKEY (E. COLI INJECTION). HUMAN (ACUTE LEUKEMIA). SOLUBLE FIBRIN IN DIC. → Non-adherent/soluble fibrin, no platelets. Blood exposed to excess tissue factor Endothelial damage Tissue factor expression by monocytes Massive tissue/organ injury

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DISSEMINATED INTRAVASCULAR COAGULATION

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  1. DISSEMINATED INTRAVASCULAR COAGULATION

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

  3. 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 CAUSES OF DIC

  4. MONOCYTE + ENDOTOXIN SMALL VESSEL LARGE VESSEL MONOCYTE VASCULAR SUBENDOTHELIUM AND CIRCULATING MONOCYTES ARE POTENTIAL SOURCES OF TISSUE FACTOR Am J Pathol 1989; 134:1087-97

  5. Control 5 nM TNF x 90 min 5 nM TNF x 24h INFLAMMATORY CYTOKINES INDUCE GAPS IN ENDOTHELIAL MONOLAYER J Exp Med 1989;169:1977-91 • Cytokine-induced endothelial damage in the microcirculation exposes blood to a large pool of subendothelial tissue factor

  6. Tissue factor mRNA Thrombin BACTERIAL LIPOPOLYSACCHARIDE INDUCES TISSUE FACTOR mRNA EXPRESSION IN HEALTHY VOLUNTEERS 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. Urokinase Tissue factor tPA Elastase Cytokines LEUKEMIC CELLS EXPRESS A VARIETY OF PROCOAGULANT AND PROFIBRINOLYTIC SUBSTANCES Annexin II

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

  10. Neutrophil Extracellular Traps (NETs) • Identified in 2004 • Extracellular webs of extruded neutrophil DNA and immunoactive enzymes • Decorated with neutrophil granular proteins: neutrophil elastase, MPO, calgranulin, cathepsin G • Last-ditch effort by neutrophils to contain infections to primary site • NETs contain a variety of substances that promote clotting • They likely contribute to activation of clotting and DIC, in patients with sepsis

  11. NETosisPathway

  12. Cytokine-mediated formation of neutrophil extracellular traps (NETs) • Green: PMN granule contents • Red: chromatin J Cell Biol 2012;198:773

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

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

  15. TNF levels correlate strongly with mortality in children with infectious purpura fulminans 100 80 Under 0.15 0.15-0.50 60 0.50-1.00 Mortality (%) 40 Over 1.00 20 0 TNF level (ng/ml) NEJM 1988;319:397-400

  16. Bleeding Thrombosis Tissue necrosis COMPLICATIONS OF DIC

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

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

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

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

  21. 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 DIC

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

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

  24. 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

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

  26. 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 C

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

  28. HOMOZYGOUS PROTEIN C DEFICIENCY WITH NEONATAL PURPURA FULMINANS

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

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

  31. 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 PROTEIN C IN BACTERIAL SEPSIS F.B. Taylor et al, J Clin Invest 1987; Blood 1991; Blood 2000

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

  33. 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 DIC PATHOPHYSIOLOGY

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

  35. 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

  36. Death Is Coming

  37. 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

  38. TREAT UNDERLYING DISEASE! Clotting factor & inhibitor replacement Fresh frozen plasma Cryoprecipitate Platelets Antithrombin III concentrate? Recombinant thrombomodulin? Pharmacologic inhibitors Heparin Antifibrinolytics TREATMENT OF DIC

  39. REPLACEMENT THERAPY IN DIC

  40. Anticoagulant: UnfractionatedHeparin (low dose, eg 500 U/hr) LMWH? Antifibrinolytic: Epsilon aminocaproic acid (Amicar) Tranexamicacid No controlled trials showing benefit in DIC Antifibrinolytictherapy benefits trauma pts Convincing anecdotal evidence of benefit in individual patients Consider using in patients with life-threatening bleeding that persists despite aggressive replacement therapy PHARMACOLOGIC INHIBITORS IN DIC

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

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

  43. Coagulopathy in Trauma Patients • Multiple causes of bleeding after trauma • Tissue damage, hypothermia, hemodilution • Some patients become overtly coagulopathic • Contributing factors may include • Acquired protein C deficiency • Shedding of endothelial heparin-like molecules • Platelet “exhaustion” • Accelerated fibrinolysis

  44. Tranexamic acid reduces all-cause mortality in major trauma: The CRASH Trial Lancet 2010;376:23

  45. Delay in administering antifibrinolytic reduces chance of survival after major trauma Odds ratio for survival Treatment Delay (min) Lancet 2018;391:125

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