Current Infectious Disease Reports

, Volume 3, Issue 5, pp 413–418

The role of protein C in sepsis

  • Mark R. Looney
  • Michael A. Matthay
Article
  • 24 Downloads

Abstract

During the past 15 years, several anti-inflammatory treatments have failed to reduce mortality in patients with severe sepsis. However, recent evidence indicates that coagulation abnormalities in sepsis may play a major role in the pathogenesis of multiple organ failure and the high mortality rate in patients with severe sepsis. Interestingly, blockade of the coagulant pathway can inhibit both procoagulant and proinflammatory pathways in sepsis. Protein C, a natural anticoagulant, interrupts several of the pathophysiologic pathways in sepsis. Acquired protein C deficiency is present in the majority of septic patients and is associated with unfavorable outcomes. Protein C replacement therapy was effective in preclinical animal models of sepsis in reducing end-organ damage and mortality. Recent clinical trials of protein C replacement in human meningococcemia resulted in a markedly decreased morbidity and mortality. And, most importantly, in a recently completed large, randomized trial of activated protein C treatment in severe sepsis, mortality was reduced from 30.8% in the placebo group to 24.7% in the treatment group at 28 days. Thus, there is new evidence that mortality can be reduced among patients with severe sepsis through the use of a new therapy that inhibits the procoagulant and the inflammatory cascades.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Friedman G, Silva E, Vincent J: Has the mortality of septic shock changed with time? Crit Care Med 1998, 26:2078–2086.PubMedCrossRefGoogle Scholar
  2. 2.
    Wheeler AP, Bernard GR: Treating patients with severe sepsis. N Engl J Med 1999, 340:207–214.PubMedCrossRefGoogle Scholar
  3. 3.
    Bernard GR, Vincent J-L, Laterre P-F, et al.: Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001, 344:699–709.PubMedCrossRefGoogle Scholar
  4. 4.
    Parrillo JE: Pathogenetic mechanisms of septic shock. N Engl J Med 1993, 328:1471–1477.PubMedCrossRefGoogle Scholar
  5. 5.
    van der Poll T, Büller HR, ten Cate H, et al.: Activation of coagulation after administration of tumor necrosis factor to normal subjects. N Engl J Med 1990, 322:1622–1627.PubMedCrossRefGoogle Scholar
  6. 6.
    Bevilacqua MP, Pober JS, Majeau GR, et al.: Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium: Characterization and comparison with the actions of interleukin 1. Proc Natl Acad Sci 1986, 83:4533–4537.PubMedCrossRefGoogle Scholar
  7. 7.
    Levi M, ten Cate H, Bauer EKA, et al.: Inhibition of endotoxininduced activation of coagulation and fibrinolysis by pentoxifylline or by a monoclonal anti-tissue factor antibody in a chimpanzee model. J Clin Invest 1994, 93:114–120.PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Conway EM, Rosenberg RD: Tumor necrosis factor suppresses transcription of the thrombomodulin gene in endothelial cells. Mol Cell Biol 1988, 8:5588–5592.PubMedCentralPubMedGoogle Scholar
  9. 9.
    Boehme MWJ, Deng Y, Raeth U, et al.: Release of thrombomodulin from endothelial cells by concerted action of TNF-a and neutrophils: in vivo and in vitro studies. Immunol 1996, 87:134–140.Google Scholar
  10. 10.
    Esmon CT: The endothelial cell protein C receptor. Thromb Haemost 2000, 83:639–643.PubMedGoogle Scholar
  11. 11.
    van Hinsbergh VWM, Bertina RM, van Wijngaarden A, et al.: Activated protein C decreases plasminogen activatorinhibitor activity in endothelial cell-conditioned medium. Blood 1985, 65:444–451.PubMedGoogle Scholar
  12. 12.
    Yamamoto K, Shimokawa T, Kojima T, et al.: Regulation of murine protein C gene expression in vivo: effects of tumor necrosis factor-alpha, interleukin-1, and transforming growth factor-beta. Thromb Haemost 1999, 82:1297–1301.PubMedGoogle Scholar
  13. 13.
    Levi M, ten Cate B: Disseminated intravascular coagulation. N Engl J Med 1999, 341:586–592.PubMedCrossRefGoogle Scholar
  14. 14.
    Matthay MA: Severe sepsis-a new treatment with both anticoagulant and antiinflammatory properties [editorial]. N Eng J Med 2001, 344:759–762.CrossRefGoogle Scholar
  15. 15.
    Taylor FB, Peer GT, Lockhart MS, et al.: Endothelial cell protein C receptor plays an important role in protein C activation in vivo. Blood 2001, 97:1685–1688.PubMedCrossRefGoogle Scholar
  16. 16.
    Laszik Z, Mitro A, Taylor FB, et al.: Human protein C receptor is present primarily on endothelium of large blood vessels. Circulation 1997, 96:3633–3640.PubMedCrossRefGoogle Scholar
  17. 17.
    Esmon CT: Introduction: are natural anticoagulants candidates for modulating the inflammatory response to endotoxin?. Blood 2000, 95:1113–1116.PubMedGoogle Scholar
  18. 18.
    Esmon CT: The anticoagulant and anti-inflammatory roles of the protein C anticoagulant pathway. J Autoimmun 2000, 15:113–116.PubMedCrossRefGoogle Scholar
  19. 19.
    Grey ST, Tsuchida A, Hau H, et al.: Selective inhibitory effects of the anticoagulant activated protein C on the responses of human mononuclear phagocytes to LPS, IFN-g or phorbol ester. J Immunol 1994, 153:3664–3672.PubMedGoogle Scholar
  20. 20.
    Grey ST, Hau H, Salem HH, Hancock WW: Selective effects of protein C on activation of human monocytes by lipopolysaccharide, interferon-gamma, or PMA: modulation of effects on CD11b, and CD14 but not CD25 or CD54 induction. Transplant Proc 1993, 25:2913–2914.PubMedGoogle Scholar
  21. 21.
    Hancock WW, Grey ST, Hau L, et al.: Binding of activated protein C to a specific receptor on human mononuclear phagocytes inhibits intracellular calcium signaling and monocyte-dependent proliferative responses. Transplantation 1995, 60:1525–1532.PubMedCrossRefGoogle Scholar
  22. 22.
    Grinnel BW, Hermann RB, Yan SB: Human protein C inhibits selectin-mediated cell adhesion: role of unique fucosylated oligosaccharide. Glycobiology 1994, 4:221–225.CrossRefGoogle Scholar
  23. 23.
    Joyce DE, Gelbert L, Ciaccia A, et al.: Gene expression profile of antithrombotic protein C defines new mechanisms modulating inflammation and apoptosis. J Biol Chem 2001, 276:11199–11203.PubMedCrossRefGoogle Scholar
  24. 24.
    Papathanassoglou ED, Moynihan JA, Ackerman MH: Does programmed cell death (apoptosis) play a role in the development of multiple organ dysfunction in critically ill patients? a review and a theoretical framework. Crit Care Med 2000, 28:537–549.PubMedCrossRefGoogle Scholar
  25. 25.
    Fisher CJ, Yan SB: Protein C levels as a prognostic indicator of outcome in sepsis and related diseases. Crit Care Med 2000, 28:S49–S56.PubMedCrossRefGoogle Scholar
  26. 26.
    Fourrier F, Chopin C, Goudemand J, et al.: Septic shock, multiple organ failure, and disseminated intravascular coagulation: compared patterns of antithrombin III, protein C, and protein S deficiencies. Chest 1992, 101:816–823.PubMedCrossRefGoogle Scholar
  27. 27.
    Hartman DL, Helterbrand JD, Bernard GR: Protein C (PC) levels in sepsis: association with mortality. Am J Respir Crit Care Med 1997, 155:A708.Google Scholar
  28. 28.
    Lorente JA, Garcia-Frade LJ, Landin L, et al.: Time course of hemostatic abnormalities in sepsis and its relation to outcome. Chest 1993, 103:1536–1542.PubMedCrossRefGoogle Scholar
  29. 29.
    Hesselvik JF, Malm J, Dahlback B, et al.: Protein C, protein S, and C4b-binding protein in severe infection and septic shock. Thromb Haemost 1991, 65:126–129.PubMedGoogle Scholar
  30. 30.
    Fijnvandraat K, Derkx B, Peters M, et al.: Coagulation activation and tissue necrosis in meningococcal septic shock: severely reduced protein C levels predict a high mortality. Thromb Haemost 1995, 73:15–20.PubMedGoogle Scholar
  31. 31.
    Powars D, Larsen R, Johnson J, et al.: Epidemic meningococcemia and purpura fulminans with induced protein C deficiency. Clin Infect Dis 1993, 17:254–261.PubMedCrossRefGoogle Scholar
  32. 32.
    Mesters RM, Helterbrand J, Utterback BG, et al.: Prognostic value of protein C concentrations in neutropenic patients at high risk of severe septic complications. Crit Care Med 2000, 28:2209–2216.PubMedCrossRefGoogle Scholar
  33. 33.
    Taylor FB, Chang A, Esmon CT, et al.: Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon. J Clin Invest 1987, 79:918–925.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Hirose K, Okajima K, Taoka Y, et al.: Activated protein C reduces the ischemia/reperfusion-induced spinal cord injury in rats by inhibiting neutrophil activation. Ann Surgery 2000, 232:272–280.CrossRefGoogle Scholar
  35. 35.
    White B, Livingstone W, Murphy C, et al.: An open-label study of the role of adjuvant hemostatic support with protein C replacement therapy in purpura fulminans-associated meningococcemia. Blood 2000, 96:3719–3724.PubMedGoogle Scholar
  36. 36.
    Alberio L, Lämmle B, Esmon CT: Protein C replacement in severe meningococcemia: rationale and clinical experience. Clin Infect Dis 2001, 32:1338–1346.PubMedCrossRefGoogle Scholar
  37. 37.
    Dickneite G: Antithrombin III in animal models of sepsis and organ failure. Semin Thromb Hemost 1998, 24:61–69.PubMedCrossRefGoogle Scholar
  38. 38.
    Minnema MC, Chang ACK, Jansen PM, et al.: Recombinant human antithrombin III improves survival and attenuates inflammatory responses in babboons lethally challenged with Escherichia coli. Blood 2000, 95:1117–1123.PubMedGoogle Scholar
  39. 39.
    Opal SM: Therapeutic rationale for antithrombin III in sepsis. Crit Care Med 2000, 28:S34–S37.PubMedCrossRefGoogle Scholar
  40. 40.
    Eisele B, Lamy M, Thijs LG, et al.: Antithrombin III in patients with severe sepsis. A randomized, placebo-controlled, double-blind multicenter trial plus a meta-analysis on all randomized, placebo-controlled, double-blind trials with antithrombin III in severe sepsis Intensive Care Med. 1998, 24:663–672.PubMedCrossRefGoogle Scholar
  41. 41.
    Park CT, Creasey AA, Wright SD: Tissue factor pathway inhibitor blocks cellular effects of endotoxin by binding to endotoxin and interfering with transfer to CD14. Blood 1997, 89:4268–4274.PubMedGoogle Scholar
  42. 42.
    Creasy AA, Chang AC, Feigen L, et al.: Tissue factor pathway inhibitor reduces mortality from Escherichia coli septic shock. J Clin Invest 1993, 91:2850–2856.CrossRefGoogle Scholar
  43. 43.
    Camerota AJ, Creasy AA, Patla V, et al.: Delayed treatment with recombinant human tissue factor pathway inhibitor improves survival in rabbits with gram-negative peritonitis. J Infect Dis 1998, 177:668–676.PubMedCrossRefGoogle Scholar
  44. 44.
    Abraham E: Tissue factor inhibition and clinical trial results of tissue factor pathway inhibitor in sepsis. Crit Care Med 2000, 28:S31–S33.PubMedCrossRefGoogle Scholar
  45. 45.
    The Acute Respiratory Distress Syndrome Network: Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000, 342:1301–1308.CrossRefGoogle Scholar
  46. 46.
    Ware LB, Matthay MA: The acute respiratory distress syndrome. N Engl J Med 2000, 342:1334–1349.PubMedCrossRefGoogle Scholar

Copyright information

© Current Science Inc 2001

Authors and Affiliations

  • Mark R. Looney
    • 1
  • Michael A. Matthay
    • 1
  1. 1.Cardiovascular Research InstituteUniversity of CaliforniaSan FranciscoUSA

Personalised recommendations