Anticoagulation Proteins C and S

  • Charles T. Esmon
  • Silvana Vigano-D’Angelo
  • Armando D’Angelo
  • Philip C. Comp

Abstract

Proteins C and S are two vitamin K-dependent plasma proteins that work in concert as a natural anticoagulant system. Activated protein C is the proteolytic component of the complex and protein S serves as an activated protein C binding protein that is essential for assembly of the anticoagulant complex on cell surfaces. The anticoagulant activity is expressed through the selective inactivation of Factors Va and Villa. Many patients deficient in proteins C and S have been described and have an associated thrombotic tendency, but not all heterozygous protein C and S deficient individuals experience thrombotic complications. Multiple mechanisms and/or drugs can lead to acquired deficiencies of these proteins: oral anticoagulation, liver disease, DIC and in the case of protein S, lupus erythematosus, nephrotic syndrome, pregnancy and certain hormones. The anticoagulant activity of protein C decreases rapidly after administration of warfarin (i.e., with a time course similar to Factor VII). This rapid decrease may lead to a transient imbalance and contribute to coumarin induced skin necrosis. Protein S antigen levels do not decrease as rapidly, but protein S functional levels are often low in patients with an acute thrombus. The discrepancy between antigen and function results from elevations in C4b-binding protein, which complexes reversibly with protein S. Unlike free protein S, the complex does not function in the anticoagulant pathway. The available information all suggest that deficiency of protein C and protein S should be considered a risk factor contributing to recurrent thrombotic disease and that the function of these proteins is altered by many common clinical conditions which have associated an increased risk of thrombosis.

Keywords

Anticoagulant Activity Skin Necrosis Common Clinical Condition Anticoagulant Pathway Hemostatic Balance 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    R. D. Rosenberg, and J. S. Rosenberg, Natural anticoagulant mechanisms, J. Clin. Invest. 74:1 (1984).PubMedCrossRefGoogle Scholar
  2. 2.
    C. T. Esmon, Protein C., in: “Progress in Hemostasis and Thrombosis, ” T. Spaet, ed., Vol. 7, pp. 25–54, Grune & Stratton, New York, NY (1984).Google Scholar
  3. 3.
    D. M. Stern, P. P. Nawroth, K. Harris, and C.T. Esmon, Cultured bovine aortic endothelial cells promote activated protein C- protein S-mediated inactivation of factor Va, J. Biol. Chem. 261:713 (1986).PubMedGoogle Scholar
  4. 4.
    I. M. Nilsson, H. Ljungner, and L. Tengborn, Two different mechanisms in patients with venous thrombosis and defective fibrinolysis: low concentrations of plasminogen activation or increased concentration of plasminogen activator inhibitor, Br. Med. J. 290:1453 (1985).CrossRefGoogle Scholar
  5. 5.
    P.C. Comp, Hereditary disorders predisposing to thrombosis, in: “Pro- gress in Hemostasis and Thrombosis, ” B. Coller, ed., Grune & Stratton, New York, NY (in press).Google Scholar
  6. 6.
    J. H. Griffin, Clinical studies of protein C, Sem. Thromb. Hemostas. 10:162 (1984).CrossRefGoogle Scholar
  7. 7.
    A. W. Broekmans, and H. M. Bertina, Protein C, in: “Recent Advances in Blood Coagulation, ” L. Pollen, ed., pp. 127–137, Churchill Livingstone, New York, NY (1980).Google Scholar
  8. 8.
    B. Laemmli, and H. J. Griffin, Formation of the fibrin clot: the bal- ance of procoagulant and inhibitory factors, Clinics in Hematol. 14:281 (1985).Google Scholar
  9. 9.
    L. H. Clouse, and P. C. Comp, The regulation of hemostasis: The pro- tein C system, N. Engl. J. Med. 314:1298 (1986).PubMedCrossRefGoogle Scholar
  10. 10.
    W. Kisiel, W. M. Canfield, E. H. Ericsson, and E. W. Davie, Anticoagu- lant properties of bovine plasma protein C following activation by thrombin, Biochemistry 16:5824 (1977).PubMedCrossRefGoogle Scholar
  11. 11.
    F. J. Walker, P. W. Sexton, and C. T. Esmon, Inhibition of blood coagu- lation by activated protein C through selective inactivation of activated factor V, Biochem. Biophys. Acta 571:333 (1979).PubMedCrossRefGoogle Scholar
  12. 12.
    R. A. Marlar, A. J. Kleiss, and J. H. Griffin, Mechanism of action of human activated protein C, a thrombin-dependent anticoagulant enzyme, JBlood 59: 1067 (1982).Google Scholar
  13. 13.
    K. Suzuki, J. Stenflo, B. Dahlback, and B. Teodorsson, Inactivation of human coagulation factor V by activated protein C, J. Biol. Chem. 258:1914 (1983).PubMedGoogle Scholar
  14. 14.
    G. A. Vehar, and E. W. Davie, Preparation and properties of bovine factor VIII, Biochemistry 19:410 (1980).CrossRefGoogle Scholar
  15. 15.
    C. A. Fulcher, J. E. Gardiner, J. H. Griffin, and T. S. Zimmerman, Proteolytic inactivation of human factor VIII procoagulant protein by activated protein C and its analogy with factor V, Blood 63:486 (1984).PubMedGoogle Scholar
  16. 16.
    F. J. Walker, Regulation of activated protein C by protein S: The role of phospholipid in factor Va inactivation, J. Biol. Chem. 256:11128 (1981).PubMedGoogle Scholar
  17. 17.
    K. W. Harris, and C. T. Esmon, Protein S is required for bovine plate- lets to support activated protein C binding and activity, J. Biol. Chem. 260:2007 (1986).Google Scholar
  18. 18.
    F. J. Walker, Identification of a new protein involved in the regula- tion of the anticoagulant activity of activated protein C: Protein S binding protein, J. Biol. Chem. 261:10941 (1986).PubMedGoogle Scholar
  19. 19.
    C.T. Esmon, and W. G. Owen, Identification of an endothelial cell co- factor for thrombin-catalyzed activation of protein C, Proc. Natl. Acad. Sci. (USA) 78:2249 (1981).CrossRefGoogle Scholar
  20. 20.
    N. L. Esmon, L. E. DeBault, and C. T. Esmon, Proteolytic formation and properties of ycarboxyglutamic acid-domainless protein C, J. Biol. Chem. 258:5548 (1983).PubMedGoogle Scholar
  21. 21.
    H. H. Salem, I. Maruyama, H. Ishii, and P. W. Majerus, Isolation and characterization of thrombomodulin from human placenta, J. Biol. Chem. 259:12246 (1984).PubMedGoogle Scholar
  22. 22.
    C. T. Esmon, N. L. Esmon, and K. W. Harris, Complex formation between thrombin and thrombomodulin inhibits both thrombin-catalyzed fibrin formation and factor V activation, J. Biol. Chem. 257:7944 (1982).PubMedGoogle Scholar
  23. 23.
    I. Maruyama, H. H. Salem, H. Ishii, and P. W. Majerus, Human thrombo- modulin is not an efficient inhibitor of procoagulant activity of thrombin, J. Clin. Invest. 75:987 (1985).PubMedCrossRefGoogle Scholar
  24. 24.
    E. A. Thompson, and H. H. Salem, Inhibition by human thrombomodulin of factor Xa-mediated cleavage of prothrombin, J. Clin. Invest. 78:13 (1986).PubMedCrossRefGoogle Scholar
  25. 25.
    B. Dahlback, and J. Stenflo, High molecular weight complex in human plasma between vitamin K-dependent protein S and complement component C4b-binding protein, Proc. Natl. Acad. Sci. (USA) 78:2512 (1981).CrossRefGoogle Scholar
  26. 26.
    B. Dahlback, Interaction between vitamin K-dependent protein S and the complement protein, C4b-binding protein: a link between coagulation and the complement system, Sem. Thromb. Haemost. 10:139 (1984).CrossRefGoogle Scholar
  27. 27.
    P. C. Comp, R. R. Nixon, M. R. Cooper, and C. T. Esmon, Familial pro- tein S deficiency is associated with recurrent thrombosis, J. Clin. Invest. 74:2082 (1984).PubMedCrossRefGoogle Scholar
  28. 28.
    R. M. Bertina, A. van Wijngaarden, J. Reinalda-Poot, and V. J. J. Bomm, Determination of plasma protein S — the protein cofactor of activated protein C, Thromb. Haemost. 53:268 (1985).PubMedGoogle Scholar
  29. 29.
    B. Dahlback, Inhibition of protein Ca cofactor function of human and bovine protein S by C4b-binding protein, J. Biol. Chem. 261:12022 (1986).PubMedGoogle Scholar
  30. 30.
    A. W. Broekmans, R. M. Bertina, J. Reinalda-Poot, L. Engesser, H. P. Muller, J. A. Leeuw, J. J. Michiels, E. J. P. Brommer, and E. Briet, Hereditary protein S deficiency and venous thromboembolism: A study in three Dutch families, Thromb. Haemost. 53:273 (1985).PubMedGoogle Scholar
  31. 31.
    H. P. Schwartz, P. Fischer, M. A. Batard, and J. H. Griffin, Plasma protein S deficiency in familial thrombotic disease, Blood 64:1297 (1984).Google Scholar
  32. 32.
    P. C. Comp, D. Doray, D. Patton, and C. T. Esmon, An abnormal plasma distribution of protein S occurs in functional protein S deficiency, Blood 67:504 (1986).PubMedGoogle Scholar
  33. 33.
    U. Seligsohn, A. Berger, M. Abend, L. Rubin, D. Attias, A. Zivelin, and S. I. Rapaport, Homozygous protein C deficiency manifested by massive venous thrombosis in the newborn, N. Engl. J. Med. 310:559 (1984).PubMedCrossRefGoogle Scholar
  34. 34.
    E. Marciniak, H. D. Wilson, and R. A. Marlar, Neonatal purpura fulmi- nans: a genetic disorder related to the absence of protein C in the blood, Blood 65:15 (1984).Google Scholar
  35. 35.
    J. P. Miletich, and G. J. Broze, Jr., Plasma protein C antigen in the normal population: What is deficiency? Circulation (abstr.), (in press)Google Scholar
  36. 36.
    P. C. Comp, S. Vigano, A. D’Angelo, G. Thurnau, C. Kaufman, and C. T. Esmon, Acquired protein S deficiency occurs in pregnancy, the nephrotic syndrome and acute systemic lupus erythematosus, Blood 66:348a (abstr. #1279) (1985).Google Scholar
  37. 37.
    L. M. Boerger, P. Morris, G. Thurnau, C. T. Esmon, and P. C. Comp, Oral contraceptives and gender influence protein S status, Blood (in press).Google Scholar
  38. 38.
    P. C. Comp, G. R. Thurnau, J. Welsh, and C. T. Esmon, Functional pro- tein S levels are reduced during pregnancy, Blood 68:881 (1986).PubMedGoogle Scholar
  39. 39.
    P. P. Nawroth, D. A. Handley, C. T. Esmon, and D. M. Stern, Interleukin 1 induces endothelial cell procoagulant while suppressing cell surface anticoagulant activity, Proc. Natl. Acad. Sci. (USA) 83:3460 (1986).CrossRefGoogle Scholar
  40. 40.
    P. P. Nawroth, and D. M. Stern, Modulation of endothelial cell hemosta- tic properties by tumor necrosis factor, J. Exp. Med. 163:740 (1986).PubMedCrossRefGoogle Scholar
  41. 41.
    K. L. Moore, S. P. Andreoli, N. L. Esmon, C. T. Esmon, and N. U. Bang, Endotoxin enhances tissue factor and suppresses thrombomodulin expression on human vascular endothelium in vitro, J. Clin. Invest, (in press).Google Scholar
  42. 42.
    F. R. Rickles, J. Levin, J. A. Hardin, C. F. Barr, and M. E. Conrad, Tissue factor generation by human mononuclear cells: Effects of endotoxin and dissociation of tissue factor generation from mito-genic response, J. Lab. Clin. Med. 89:792 (1977).PubMedGoogle Scholar
  43. 43.
    S. V. D’Angelo, P. C. Comp, C. T. Esmon, and A. D’Angelo, Relationship between protein C antigen and anticoagulant activity during oral anticoagulation and in selected disease states, J. Clin. Invest. 77:416 (1986).PubMedCrossRefGoogle Scholar
  44. 44.
    A. D’Angelo, C. T. Esmon, P. C. Comp, C. Boyer, P. M. Mannucci, and S. Vigano-D’Angelo, The half life of protein S is much longer than protein C, Blood 66:349a (abstr.) (1985).Google Scholar
  45. 45.
    A. W. Broekmans, R. M. Bertina, E. A. Loeliger, V. Hofmann, and H.-G. Klingemann, Protein C and the development of skin necrosis during anticoagulant therapy, Thromb. Haemost. 49:244 (1983).Google Scholar
  46. 46.
    W. G. McGehee, T. A. Klotz, D. J. Epstein, and S. I. Rapaport, Couma- din necrosis associated with hereditary protein C deficiency, Ann. Int. Med. 100:59 (1984).CrossRefGoogle Scholar
  47. 47.
    M. Samama, M. H. Horellou, J. Soria, J. Conard, and G. Nicolas, Suc- cessful progressive anticoagulation in a severe protein C deficiency and previous skin necrosis at the initiation of oral anticoagulation treatment, Thromb. Haemost. 51:132 (1984).PubMedGoogle Scholar
  48. 48.
    N. P. Zauber, and M. W. Stark, Successful warfarin anticoagulation de- spite protein C deficiency and a history of warfarin necrosis, Ann. Intern. Med. 104:659 (1986).PubMedCrossRefGoogle Scholar
  49. 49.
    F. J. Kazmier, Thromboembolism, coumarin necrosis and protein C, Mayo Clin. Proc. 60:673 (1985).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1987

Authors and Affiliations

  • Charles T. Esmon
    • 1
  • Silvana Vigano-D’Angelo
    • 1
  • Armando D’Angelo
    • 1
  • Philip C. Comp
    • 1
  1. 1.Thrombosis/Hematology, Oklahoma Medical Research Foundation and Department of MedicineUniversity of Oklahoma HealthSciences CenterOklahoma CityUK

Personalised recommendations