Update on Physiological Anticoagulant Factor Concentrates in Patients with Sepsis

  • M. Levi
  • T. Van Der Poll
Conference paper


Patients with severe sepsis have systemic activation of the inflammatory system and of coagulation. Increasing evidence points to an extensive cross-talk between these two systems, whereby inflammation not only leads to activation of coagulation, but coagulation also considerably affects inflammatory activity [1]. The intricate relationship between inflammation and coagulation may have major consequences for the pathogenesis of microvascular failure and subsequent multiple organ failure, as a result of severe infection and the associated systemic inflammatory response. Molecular pathways that contribute to inflammation-induced activation of coagulation and modulation of inflammation by coagulation factors have been precisely identified. Endothelial-bound anticoagulant mechanisms, in particular the protein C system, tissue factor pathway inhibitor (TFPI) and the antithrombin system, play important roles in this respect [2]. These findings have resulted in the development of physiological anticoagulant factor concentrates for (adjunctive) treatment in patients with sepsis. In this chapter, we briefly provide new insights from preclinical research with these anticoagulant factors in sepsis and an update of recent clinical findings.


Severe Sepsis Tissue Factor Pathway Inhibitor Drotrecogin Alfa Soluble Thrombomodulin Recombinant Human Soluble Thrombomodulin 
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  1. 1.
    Levi M, van der Poll T, Buller HR (2004) Bidirectional relation between inflammation and coagulation. Circulation 109: 2698–2704CrossRefPubMedGoogle Scholar
  2. 2.
    Levi M, van der Poll T (2008) The role of natural anticoagulants in the pathogenesis and management of systemic activation of coagulation and inflammation in critically ill patients. Semin Thromb Hemost 34: 459–468CrossRefPubMedGoogle Scholar
  3. 3.
    Opal SM, Esmon CT (2003) Bench-to-bedside review: functional relationships between coagulation and the innate immune response and their respective roles in the pathogenesis of sepsis. Crit Care 7: 23–38CrossRefPubMedGoogle Scholar
  4. 4.
    Kobayashi M, Shimada K, Ozawa T (1990) Human recombinant interleukin-1 beta-and tumor necrosis factor alpha-mediated suppression of heparin-like compounds on cultured porcine aortic endothelial cells. J Cell Physiol 144: 383–390CrossRefPubMedGoogle Scholar
  5. 5.
    Esmon CT (2001) Role of coagulation inhibitors in inflammation. Thromb Haemost 86: 51–56PubMedGoogle Scholar
  6. 6.
    Esmon CT (1987) The regulation of natural anticoagulant pathways. Science 235: 1348–1352CrossRefPubMedGoogle Scholar
  7. 7.
    Esmon CT (2000) The endothelial cell protein C receptor. Thromb Haemost 83: 639–643PubMedGoogle Scholar
  8. 8.
    Perez-Casal M, Downey C, Fukudome K, Marx G, Toh CH (2005) Activated protein C induces the release of microparticle-associated endothelial protein C receptor. Blood 105: 1515–1522CrossRefPubMedGoogle Scholar
  9. 9.
    Faust SN, Levin M, Harrison OB, et al (2001) Dysfunction of endothelial protein C activation in severe meningococcal sepsis. N Engl J Med 345: 408–416CrossRefPubMedGoogle Scholar
  10. 10.
    Taylor FBJ, Dahlback B, Chang AC, et al (1995) Role of free protein Sand C4b binding protein in regulating the coagulant response to Escherichia coli. Blood 86: 2642–2652PubMedGoogle Scholar
  11. 11.
    De Pont AC, Bakhtiari K, Hutten BA, et al (2006) Endotoxaemia induces resistance to activated protein C in healthy humans. Br J Haematol 134: 213–219CrossRefPubMedGoogle Scholar
  12. 12.
    de Jonge E, Dekkers PE, Creasey AA, et al (2000) Tissue factor pathway inhibitor (TFPI) dose-dependently inhibits coagulation activtion without influencing the fibrinolytic and cytokine response during human endotoxemia. Blood 95: 1124–1129PubMedGoogle Scholar
  13. 13.
    Creasey AA, Chang AC, Feigen L, Wun TC, Taylor FBJ, Hinshaw LB (1993) Tissue factor pathway inhibitor reduces mortality from Escherichia coli septic shock. J Clin Invest 91: 2850–2856CrossRefPubMedGoogle Scholar
  14. 14.
    Opal SM (2003) Interactions between coagulation and inflammation. Scand J Infect Dis 35: 545–554CrossRefPubMedGoogle Scholar
  15. 15.
    Uchiba M, Okajima K, Murakami K (1998) Effects of various doses of antithrombin III on endotoxin-induced endothelial cell injury and coagulation abnormalities in rats. Thromb Res 89: 233–241CrossRefPubMedGoogle Scholar
  16. 16.
    Okajima K (2001) Regulation of inflammatory responses by natural anticoagulants. Immunol Rev 184: 258–274CrossRefPubMedGoogle Scholar
  17. 17.
    Hancock WW, Grey ST, Hau L, et al (1995) Binding of activated protein C to a specific receptor on human mononuclear phagocytes inhibits intracellular calcium signaling and monocyte-dependent proliferative responses. Transplantation 60: 1525–1532CrossRefPubMedGoogle Scholar
  18. 18.
    Levi M, Dorffler-Melly J, Reitsma PH, et al (2003) Aggravation of endotoxin-induced dis seminated intravascular coagulation and cytokine activation in heterozygous protein C deficient mice. Blood 101: 4823–4827CrossRefPubMedGoogle Scholar
  19. 19.
    Esmon CT (2002) New mechanisms for vascular control of inflammation mediated by natural anticoagulant proteins. J Exp Med 196: 561–564CrossRefPubMedGoogle Scholar
  20. 20.
    Riewald M, Petrovan RJ, Donner A, Mueller BM, Ruf W (2002) Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science 296: 1880–1882CrossRefPubMedGoogle Scholar
  21. 21.
    Oganesyan V, Oganesyan N, Terzyan S, et al (2002) The crystal structure of the endothelial protein C receptor and a bound phospholipid. J Biol Chem 277: 24851–24854CrossRefPubMedGoogle Scholar
  22. 22.
    Taylor FBJ, Stearns-Kurosawa DJ, Kurosawa S, et al (2000) The endothelial cell protein C receptor aids in host defense against Escherichia coli sepsis. Blood 95: 1680–1686PubMedGoogle Scholar
  23. 23.
    Feistritzer C, Sturn DH, Kaneider NC, Djanani A, Wiedermann CJ (2003) Endothelial protein C receptor-dependent inhibition of human eosinophil chemotaxis by protein C. J Allergy Clin Immunol 112: 375–381CrossRefPubMedGoogle Scholar
  24. 24.
    Hoffmann IN, Vollmar B, Laschke MW, et al (2004) Microhemodynamic and cellular mechanisms of activated protein C action during endotoxemia. Crit Care Med 32: 1011–1017CrossRefPubMedGoogle Scholar
  25. 25.
    Nick JA, Coldren CD, Geraci MW, et al (2004) Recombinant human activated protein reduces human endotoxin-induced pulmonary inflammation via inhibition of neutrophil chemotaxis. Blood 104: 3878–3885CrossRefPubMedGoogle Scholar
  26. 26.
    Finigan JH, Dudek SM, Singleton PA, et al (2005) Activated protein C mediates novel lung endothelial barrier enhancement: role of sphingosine I-phosphate receptor transactivation. J Biol Chem 280: 17286–17293CrossRefPubMedGoogle Scholar
  27. 27.
    Mosnier LO, Zlokovic BV, Griffin JH (2007) The cytoprotective protein C pathway. Blood 109: 3161–3172CrossRefPubMedGoogle Scholar
  28. 28.
    Levi M, de Ionge E, van der Poll T (2001) Rationale for restoration of physiological anticoagulant pathways in patients with sepsis and disseminated intravascular coagulation. Crit Care Med 29: S90–S94CrossRefPubMedGoogle Scholar
  29. 29.
    Minnema MC, Chang AC, Jansen PM, et al (2000) Recombinant human antithrombin III improves survival and attenuates inflammatory responses in baboons lethally challenged with Escherichia coli. Blood 95: 1117–1123PubMedGoogle Scholar
  30. 30.
    Levi M, de Ionge E, van der Poll T, ten Cate H (1999) Disseminated intravascular coagulation: State of the art. Thromb Haemost 82: 695–705PubMedGoogle Scholar
  31. 31.
    Warren BL, Eid A, Singer P, et al (2001) Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA 286: 1869–1878CrossRefPubMedGoogle Scholar
  32. 32.
    Kienast J, Juers M, Wiedermann CJ, et al (2006) Treatment effects of high-dose antithrombin without concomitant heparin in patients with severe sepsis with or without disseminated intravascular coagulation. J Thromb Haemost 4: 90–97CrossRefPubMedGoogle Scholar
  33. 33.
    Blauhut B, Kramar H, Vinazzer H, Bergmann H (1985) Substitution of antithrombin III in shock and DIC: a randomized study. Thromb Res 39: 81–89CrossRefPubMedGoogle Scholar
  34. 34.
    Horie S, Ishii H, Kazama M (1990) Heparin-like glycosaminoglycan is a receptor for antithrombin III-dependent but not for thrombin-dependent prostacyclin production in human endothelial cells. Thromb Res 59: 895–904CrossRefPubMedGoogle Scholar
  35. 35.
    Bishop JR, Schuksz M, Esko JD (2007) Heparan sulphate proteoglycans fine-tune mammalian physiology. Nature 446: 1030–1037CrossRefPubMedGoogle Scholar
  36. 36.
    Parish CR (2006) The role of heparan sulphate in inflammation. Nat Rev Immunol 6: 633–643CrossRefPubMedGoogle Scholar
  37. 37.
    Laterre PF (2007) Clinical trials in severe sepsis with drotrecogin alfa (activated). Crit Care 11 (Suppl 5): 55CrossRefGoogle Scholar
  38. 38.
    Bernard GR, Ely EW, Wright TJ, et al (2001) Safety and dose relationship of recombinant human activated protein C for coagulopathy in severe sepsis. Crit Care Med 29: 2051–2059CrossRefPubMedGoogle Scholar
  39. 39.
    Bernard GR, Vincent JL, Laterre PF, et al (2001) Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 344: 699–709CrossRefPubMedGoogle Scholar
  40. 40.
    Dhainaut JF, Yan SB, Joyce DE, et al (2004) Treatment effects of drotrecogin alfa (activated) in patients with severe sepsis with or without overt disseminated intravascular coagulation. J Thromb Haemost 2: 1924–1933CrossRefPubMedGoogle Scholar
  41. 41.
    Abraham E, Laterre PF, Garg R, et al (2005) Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med 353: 1332–1341CrossRefPubMedGoogle Scholar
  42. 42.
    Levi M, Levy M, Williams MD, et al (2007) Prophylactic heparin in patients with severe sepsis treated with drotrecogin alfa (activated). Am J Respir Crit Care Med 176: 483–490CrossRefPubMedGoogle Scholar
  43. 43.
    Wiedermann CJ, Kaneider NC (2005) A meta-analysis of controlled trials of recombinant human activated protein C therapy in patients with sepsis. BMC Emerg Med 5: 7CrossRefPubMedGoogle Scholar
  44. 44.
    Fumagalli R, Mignini MA (2007) The safety profile of drotrecogin alfa (activated). Crit Care 11 (Suppl 5): S6CrossRefPubMedGoogle Scholar
  45. 45.
    Wheeler A, Steingrub J, Schmidt GA, et al (2008) A retrospective observational study of drotrecogin alfa (activated) in adults with severe sepsis: comparison with a controlled clinical trial. Crit Care Med 36: 14–23CrossRefPubMedGoogle Scholar
  46. 46.
    Schultz MJ, Levi M (2006) Prescription of rh-APC differs substantially among western European countries. Intensive Care Med 32: 630–631CrossRefPubMedGoogle Scholar
  47. 47.
    Barie PS (2007) “All in” for a huge pot: the PROWESS-SHOCK trial for refractory septic shock. Surg Infect (Larchmt) 8: 491–494CrossRefGoogle Scholar
  48. 48.
    Saito H, Maruyama I, Shimazaki S, et al (2007) Efficacy and safety of recombinant human soluble thrombomodulin (ART-123) in disseminated intravascular coagulation: results of a phase III, randomized, double-blind clinical trial. J Thromb Haemost 5: 31–41CrossRefPubMedGoogle Scholar
  49. 49.
    Abraham E, Reinhart K, Svoboda P, et al (2001) Assessment of the safety of recombinant tissue factor pathway inhibitor in patients with severe sepsis: a multicenter, randomized, placebo-controlled, single-blind, dose escalation study. Crit Care Med 29: 2081–2089CrossRefPubMedGoogle Scholar
  50. 50.
    Abraham E, Reinhart K, Opal S, et al (2003) Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. JAMA 290: 238–247CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science + Business Media Inc. 2010

Authors and Affiliations

  • M. Levi
    • 1
  • T. Van Der Poll
    • 2
  1. 1.Department of Medicine (F-4)Academic Medica CenterAmsterdamNetherlands
  2. 2.Center for Experimental and Molecular MedicineCenter of Infection and Immunity Academic Medical CenterAmsterdamNetherlands

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