Advertisement

Protein-C-Pathway

  • C.-E. Dempfle
Conference paper

Zusammenfassung

Protein C ist das Proenzym einer Serinproteinase, wird von der Leber synthetisiert und Vitamin-K-abhängig mit γ-Carboxyglutamin-Gruppen (Gla) ausgestattet [23]. Die Aktivierung erfolgt durch Abspaltung eines aus 12 Aminosäuren bestehenden Aktivierungspeptids durch Thrombin und Proteasen ähnlicher Spezifität [24].

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Literatur

  1. 1.
    Bajzar L, Nesheim M, Morser J, Tracy PB (1998) Both cellular and soluble forms of thrombomodulin inhibit fibrinolysis by potentiating the activation of thrombin-activable fibrinolysis inhibitor. J Biol Chem 273: 2792–2798PubMedCrossRefGoogle Scholar
  2. 2.
    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: 699–709PubMedCrossRefGoogle Scholar
  3. 3.
    Bertina RM, Koeleman BP, Koster T et al. (1994) Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 369: 64–67PubMedCrossRefGoogle Scholar
  4. 4.
    Bouma BN, von dem Borne PA, Meijers JC (1998) Factor XI and protection of the fibrin clot against lysis — a role for the intrinsic pathway of coagulation in fibrinolysis. Thromb Haemost 80: 24–27PubMedGoogle Scholar
  5. 5.
    Briede J J, Tans G, Willems GM, Hemker HC, Lindhout T (2001) Regulation of platelet factor Va-dependent thrombin generation by activated protein C at the surface of collagen-adherent platelets. J Biol Chem 276: 7164–7168PubMedCrossRefGoogle Scholar
  6. 6.
    Dahlback B, Carlsson M, Svensson PJ (1993) Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci USA 90: 1004–1008PubMedCrossRefGoogle Scholar
  7. 7.
    De Cristofaro R, De Candia E, Landolfi R (1998) Effect of high- and low-molecular-weight heparins on thrombin-thrombomodulin interaction and protein C activation. Circulation 98: 1297–1301PubMedGoogle Scholar
  8. 8.
    de Fouw NJ, de Jong YF, Haverkate F, Bertina RM (1988) Activated protein C increases fibrin clot lysis by neutralization of plasminogen activator inhibitor — no evidence for a cofactor role of protein S. Thromb Haemost 60: 328–333Google Scholar
  9. 9.
    Elisen MG, von dem Borne PA, Bouma BN, Meijers JC (1998) Protein C inhibitor acts as a procoagulant by inhibiting the thrombomodulin-induced activation of protein C in human plasma. Blood 91: 1542–1547PubMedGoogle Scholar
  10. 10.
    Esmon CT, Owen WG (1981) Identification of an endothelial cell cofactor for thrombin-catalyzed activation of protein C. Proc Natl Acad Sci USA 78: 2249–2252PubMedCrossRefGoogle Scholar
  11. 11.
    Esmon CT, Xu J, Gu JM et al. (1999) Endothelial protein C receptor. Thromb Haemost 82: 251–258PubMedGoogle Scholar
  12. 12.
    Faust SN, Levin M, Harrison OB et al. (2001) Dysfunction of endothelial protein C activation in severe meningococcal sepsis. N Engl J Med 345: 408–416PubMedCrossRefGoogle Scholar
  13. 13.
    Franco RF, Elion J, Tavella MH, Santos SE, Zago MA (1999) The prevalence of factor V Arg306→Thr (factor V Cambridge) and factor V Arg306→Gly mutations in different human populations. Thromb Haemost 81: 312–313PubMedGoogle Scholar
  14. 14.
    Gladson CL, Groncy P, Griffin JH (1987) Coumarin necrosis, neonatal purpura fulminans, and protein C deficiency. Arch Dermatol 123:170la–1706aGoogle Scholar
  15. 15.
    Gu JM, Katsuura Y, Ferrell GL, Grammas P, Esmon CT (2001) Endotoxin and thrombin elevate rodent endothelial cell protein C receptor mRNA levels and increase receptor shedding in vivo. Blood 95: 1687–1693Google Scholar
  16. 16.
    Healy AM, Hancock WW, Christie PD,Rayburn HB, Rosenberg RD (1998) Intravascular coagulation activation in a murine model of thrombomodulin deficiency: effects of lesion size, age, and hypoxia on fibrin deposition. Blood 92: 4188–4197Google Scholar
  17. 17.
    Hockin MF, Kalafatis M, Shatos M, Mann KG (1997) Protein C activation and factor Va inactivation on human umbilical vein endothelial cells. Arterioscler Thromb Vase Biol 17: 2765–2775CrossRefGoogle Scholar
  18. 18.
    Howard TE, Marusa M, Channell C, Duncan A (1997) A patient homozygous for a mutation in the prothrombin gene 3′-untranslated region associated with massive thrombosis. Blood Coagul Fibrinolysis 8: 316–319PubMedCrossRefGoogle Scholar
  19. 19.
    Isermann B, Hendrickson SB, Zogg M et al. (2001) Endothelium-specifk loss of murine thrombomodulin disrupts the protein C anticoagulant pathway and causes juvenile-onset thrombosis. J Clin Invest 108: 537–546PubMedGoogle Scholar
  20. 20.
    Ishii H, Majerus PW (1985) Thrombomodulin is present in human plasma and urine. J Clin Invest 76: 2178–2181PubMedCrossRefGoogle Scholar
  21. 21.
    Iwashima Y, Sato T, Watanabe K et al. (1990) Elevation of plasma thrombomodulin level in diabetic patients with early diabetic nephropathy. Diabetes 39: 983–988PubMedCrossRefGoogle Scholar
  22. 22.
    Kalafatis M, Mann KG (1993) Role of the membrane in the inactivation of factor Va by activated protein C. J Biol Chem 268: 27246–27257PubMedGoogle Scholar
  23. 23.
    Kisiel W (1979) Human plasma protein C: isolation, characterization, and mechanism of activation by alpha-thrombin. J Clin Invest 64: 761–769PubMedCrossRefGoogle Scholar
  24. 24.
    Kisiel W, Ericsson LH, Davie EW (1976) Proteolytic activation of protein C from bovine plasma. Biochemistry 15: 4893–4900PubMedCrossRefGoogle Scholar
  25. 25.
    Lindahl AK, Boffa MC, Abildgaard U (1993) Increased plasma thrombomodulin in cancer patients. Thromb Haemost 69: 112–114PubMedGoogle Scholar
  26. 26.
    Mosnier LO, Meijers JC, Bouma BN (2001) Regulation of fibrinolysis in plasma by TAFI and protein C is dependent on the concentration of thrombomodulin. Thromb Haemost 85: 5–11PubMedGoogle Scholar
  27. 27.
    Neese LL, Pratt CW, Church FC (1994) Modulation of protein C inhibitor activity. Blood Coagul Fibrinolysis 5: 737–746PubMedCrossRefGoogle Scholar
  28. 28.
    Nishioka J, Ning M, Hayashi T, Suzuki K (1998) Protein C inhibitor secreted from activated platelets efficiently inhibits activated protein C on phosphatidylethanolamine of platelet membrane and microvesicles. J Biol Chem 273: 11281PubMedCrossRefGoogle Scholar
  29. 29.
    O’Brien LM, Mastri M, Fay PJ (2000) Regulation of factor Villa by human activated protein C and protein S: inactivation of cofactor in the intrinsic factor Xase. Blood 95: 1714–1720PubMedGoogle Scholar
  30. 30.
    Ohlin AK, Morser J, Ohlin H (1996) Soluble thrombomodulin antigen in plasma is increased in patients with acute myocardial infarction treated with thrombolytic therapy. Thromb Res 82: 313–322PubMedCrossRefGoogle Scholar
  31. 31.
    Petaja J, Fernandez JA, Gruber A, Griffin JH (1997) Anticoagulant synergism of heparin and activated protein C in vitro. Role of a novel anticoagulant mechanism of heparin, enhancement of inactivation of factor V by activated protein C. J Clin Invest 99: 2655–2663Google Scholar
  32. 32.
    Rappaport ES, Speights VO, Heibert B, Trowbridge A, Koops B, Montgomery RR, Marlar RA (1987) Protein C deficiency. South Med J 80: 240–242PubMedCrossRefGoogle Scholar
  33. 33.
    Rezaie AR (2001) Vitronectin functions as a cofactor for rapid inhibition of activated protein C by plasminogen activator inhibitor-1. Implications for the mechanism of profibrinolytic action of activated protein C. J Biol Chem 276: 15567–15570PubMedCrossRefGoogle Scholar
  34. 34.
    Shen L, He X, Dahlback B (1997) Synergistic cofactor function of factor V and protein S to activated protein C in the inactivation of the factor Villa - factor IXa complex — species specific interactions of components of the protein C anticoagulant system. Thromb Haemost 78: 1030–1036PubMedGoogle Scholar
  35. 35.
    Smirnov MD, Safa O, Esmon NL, Esmon CT (1999) Inhibition of activated protein C anticoagulant activity by prothrombin. Blood 94: 3839–3846PubMedGoogle Scholar
  36. 36.
    Stewart RJ, Fredenburgh JC, Rischke JA, Bajzar L, Weitz JI (2000) Thrombin-activable fibrinolysis inhibitor attenuates DD(E)-mediated stimulation of plasminogen activation by reducing the affinity of DD(E) for tissue plasminogen activator. J Biol Chem 275: 36612–36620PubMedCrossRefGoogle Scholar
  37. 37.
    Suzuki K, Stenflo J, Dahlback B, Teodorsson B (1983) Inactivation of human coagulation factor V by activated protein C. J Biol Chem 258: 1914–1920PubMedGoogle Scholar
  38. 38.
    Taylor FB Jr, Peer GT, Lockhart MS, Ferrell G, Esmon CT (2001) Endothelial cell protein C receptor plays an important role in protein C activation in vivo. Blood 97: 1685–1688PubMedCrossRefGoogle Scholar
  39. 39.
    Taylor FB Jr, Stearns-Kurosawa DJ, Kurosawa S et al. (2001) The endothelial cell protein C receptor aids in host defense against Escherichia coli sepsis. Blood 95: 1680–1686Google Scholar
  40. 40.
    van de Poel RH, Meijers JC, Bouma BN (2001) C4b-binding protein inhibits the factor V-dependent but not the factor V-independent cofactor activity of protein S in the activated protein C-mediated inactivation of factor Villa. Thromb Haemost 85: 761–775Google Scholar
  41. 41.
    van de Poel RH, Meijers JC, Rosing J, Tans G, Bouma BN (2000) C4b-binding protein protects coagulation factor Va from inactivation by activated protein C. Biochemistry 39: 14543–14548Google Scholar
  42. 42.
    Vincent JL (2001) Microvascular endothelial dysfunction: a renewed appreciation of sepsis pathophysiology. Crit Care 5: S1–S5PubMedCrossRefGoogle Scholar
  43. 43.
    Walker JB, Nesheim ME (2001) A kinetic analysis of the tissue plasminogen activator and DSPAa1 cofactor activities of untreated and TAFIa-treated soluble fibrin degradation products of varying size. J Biol Chem 276: 3138–3148PubMedCrossRefGoogle Scholar
  44. 44.
    Weiler-Guettler H, Christie PD, Beeler DL et al. (1998) A targeted point mutation in thrombomodulin generates viable mice with a prethrombotic state. J Clin Invest 101: 1983–1991PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2002

Authors and Affiliations

  • C.-E. Dempfle

There are no affiliations available

Personalised recommendations