Skip to main content
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1986 Feb;77(2):416–425. doi: 10.1172/JCI112319

Relationship between protein C antigen and anticoagulant activity during oral anticoagulation and in selected disease states.

S Vigano D'Angelo, P C Comp, C T Esmon, A D'Angelo
PMCID: PMC423361  PMID: 3511097

Abstract

Protein C is a natural vitamin K-dependent plasma anticoagulant, deficiencies of which have been found in patients with recurrent thrombosis and warfarin-induced skin necrosis. To appreciate more fully the role of protein C in disease states and during oral anticoagulation, a new functional assay for protein C involving adsorption of plasma protein C on a Ca+2-dependent monoclonal antibody, elution, quantitative activation, and assessment of plasma anticoagulant activity, has been developed. When oral anticoagulation is initiated, the anticoagulant activity of protein C decreases to a greater extent than either the amidolytic or immunologic levels. During stabilized warfarin treatment, there is no correlation between either amidolytic or antigenic levels and the functional protein C activity, suggesting that measurement of protein C anticoagulant activity may be necessary to reflect adequately the anticoagulant protection afforded by this protein. In contrast, there was a strong correlation between anticoagulant and amidolytic and immunologic levels in liver failure and disseminated intravascular coagulation. Two patients with thromboembolic disease have been identified who exhibit a marked decrease in anticoagulant activity, but who have normal immunologic and amidolytic levels. Thus, this assay permits assessment of protein C in individuals who have received anticoagulant treatment and identification of a new class of protein C-deficient individuals.

Full text

PDF
419

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Barbui T., Finazzi G., Mussoni L., Riganti M., Donati M. B., Colucci M., Collen D. Hereditary dysfunctional protein C (protein C Bergamo) and thrombosis. Lancet. 1984 Oct 6;2(8406):819–819. doi: 10.1016/s0140-6736(84)90750-5. [DOI] [PubMed] [Google Scholar]
  2. Bauer K. A., Kass B. L., Beeler D. L., Rosenberg R. D. Detection of protein C activation in humans. J Clin Invest. 1984 Dec;74(6):2033–2041. doi: 10.1172/JCI111626. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bertina R. M., Broekmans A. W., van der Linden I. K., Mertens K. Protein C deficiency in a Dutch family with thrombotic disease. Thromb Haemost. 1982 Aug 24;48(1):1–5. [PubMed] [Google Scholar]
  4. Borowski M., Furie B. C., Goldsmith G. H., Furie B. Metal and phospholipid binding properties of partially carboxylated human prothrombin variants. J Biol Chem. 1985 Aug 5;260(16):9258–9264. [PubMed] [Google Scholar]
  5. Branson H. E., Katz J., Marble R., Griffin J. H. Inherited protein C deficiency and coumarin-responsive chronic relapsing purpura fulminans in a newborn infant. Lancet. 1983 Nov 19;2(8360):1165–1168. doi: 10.1016/s0140-6736(83)91216-3. [DOI] [PubMed] [Google Scholar]
  6. Broekmans A. W., Bertina R. M., Loeliger E. A., Hofmann V., Klingemann H. G. Protein C and the development of skin necrosis during anticoagulant therapy. Thromb Haemost. 1983 Jun 28;49(3):251–251. [PubMed] [Google Scholar]
  7. Broekmans A. W., Veltkamp J. J., Bertina R. M. Congenital protein C deficiency and venous thromboembolism. A study of three Dutch families. N Engl J Med. 1983 Aug 11;309(6):340–344. doi: 10.1056/NEJM198308113090604. [DOI] [PubMed] [Google Scholar]
  8. Comp P. C., Esmon C. T. Activated protein C inhibits platelet prothrombin-converting activity. Blood. 1979 Dec;54(6):1272–1281. [PubMed] [Google Scholar]
  9. Comp P. C., Esmon C. T. Recurrent venous thromboembolism in patients with a partial deficiency of protein S. N Engl J Med. 1984 Dec 13;311(24):1525–1528. doi: 10.1056/NEJM198412133112401. [DOI] [PubMed] [Google Scholar]
  10. Comp P. C., Nixon R. R., Cooper M. R., Esmon C. T. Familial protein S deficiency is associated with recurrent thrombosis. J Clin Invest. 1984 Dec;74(6):2082–2088. doi: 10.1172/JCI111632. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Comp P. C., Nixon R. R., Esmon C. T. Determination of functional levels of protein C, an antithrombotic protein, using thrombin-thrombomodulin complex. Blood. 1984 Jan;63(1):15–21. [PubMed] [Google Scholar]
  12. Cuatrecasas P. Protein purification by affinity chromatography. Derivatizations of agarose and polyacrylamide beads. J Biol Chem. 1970 Jun;245(12):3059–3065. [PubMed] [Google Scholar]
  13. Di Scipio R. G., Hermodson M. A., Yates S. G., Davie E. W. A comparison of human prothrombin, factor IX (Christmas factor), factor X (Stuart factor), and protein S. Biochemistry. 1977 Feb 22;16(4):698–706. doi: 10.1021/bi00623a022. [DOI] [PubMed] [Google Scholar]
  14. Epstein D. J., Bergum P. W., Bajaj S. P., Rapaport S. I. Radioimmunoassays for protein C and factor X. Plasma antigen levels in abnormal hemostatic states. Am J Clin Pathol. 1984 Nov;82(5):573–581. doi: 10.1093/ajcp/82.5.573. [DOI] [PubMed] [Google Scholar]
  15. Esmon C. T., Owen W. G. Identification of an endothelial cell cofactor for thrombin-catalyzed activation of protein C. Proc Natl Acad Sci U S A. 1981 Apr;78(4):2249–2252. doi: 10.1073/pnas.78.4.2249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Esmon C. T., Stenflo J., Suttie J. W. A new vitamin K-dependent protein. A phospholipid-binding zymogen of a serine esterase. J Biol Chem. 1976 May 25;251(10):3052–3056. [PubMed] [Google Scholar]
  17. Esmon N. L., DeBault L. E., Esmon C. T. Proteolytic formation and properties of gamma-carboxyglutamic acid-domainless protein C. J Biol Chem. 1983 May 10;258(9):5548–5553. [PubMed] [Google Scholar]
  18. Esmon N. L., Owen W. G., Esmon C. T. Isolation of a membrane-bound cofactor for thrombin-catalyzed activation of protein C. J Biol Chem. 1982 Jan 25;257(2):859–864. [PubMed] [Google Scholar]
  19. Estellés A., Garcia-Plaza I., Dasí A., Aznar J., Duart M., Sanz G., Pérez-Requejo J. L., España F., Jimenez C., Abeledo G. Severe inherited "homozygous" protein C deficiency in a newborn infant. Thromb Haemost. 1984 Aug 31;52(1):53–56. [PubMed] [Google Scholar]
  20. Francis R. B., Jr, Patch M. J. A functional assay for protein C in human plasma. Thromb Res. 1983 Dec 15;32(6):605–613. doi: 10.1016/0049-3848(83)90062-2. [DOI] [PubMed] [Google Scholar]
  21. Griffin J. H., Evatt B., Zimmerman T. S., Kleiss A. J., Wideman C. Deficiency of protein C in congenital thrombotic disease. J Clin Invest. 1981 Nov;68(5):1370–1373. doi: 10.1172/JCI110385. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Griffin J. H., Mosher D. F., Zimmerman T. S., Kleiss A. J. Protein C, an antithrombotic protein, is reduced in hospitalized patients with intravascular coagulation. Blood. 1982 Jul;60(1):261–264. [PubMed] [Google Scholar]
  23. Kisiel W., Canfield W. M., Ericsson L. H., Davie E. W. Anticoagulant properties of bovine plasma protein C following activation by thrombin. Biochemistry. 1977 Dec 27;16(26):5824–5831. doi: 10.1021/bi00645a029. [DOI] [PubMed] [Google Scholar]
  24. Kisiel W. Human plasma protein C: isolation, characterization, and mechanism of activation by alpha-thrombin. J Clin Invest. 1979 Sep;64(3):761–769. doi: 10.1172/JCI109521. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Laurell C. B. Quantitative estimation of proteins by electrophoresis in agarose gel containing antibodies. Anal Biochem. 1966 Apr;15(1):45–52. doi: 10.1016/0003-2697(66)90246-6. [DOI] [PubMed] [Google Scholar]
  26. Mannucci P. M., Vigano S. Deficiencies of protein C, an inhibitor of blood coagulation. Lancet. 1982 Aug 28;2(8296):463–467. doi: 10.1016/s0140-6736(82)90494-9. [DOI] [PubMed] [Google Scholar]
  27. Marciniak E., Wilson H. D., Marlar R. A. Neonatal purpura fulminans: a genetic disorder related to the absence of protein C in blood. Blood. 1985 Jan;65(1):15–20. [PubMed] [Google Scholar]
  28. Marlar R. A., Kleiss A. J., Griffin J. H. Mechanism of action of human activated protein C, a thrombin-dependent anticoagulant enzyme. Blood. 1982 May;59(5):1067–1072. [PubMed] [Google Scholar]
  29. McGehee W. G., Klotz T. A., Epstein D. J., Rapaport S. I. Coumarin necrosis associated with hereditary protein C deficiency. Ann Intern Med. 1984 Jul;101(1):59–60. doi: 10.7326/0003-4819-101-1-59. [DOI] [PubMed] [Google Scholar]
  30. Owen W. G., Esmon C. T. Functional properties of an endothelial cell cofactor for thrombin-catalyzed activation of protein C. J Biol Chem. 1981 Jun 10;256(11):5532–5535. [PubMed] [Google Scholar]
  31. Owen W. G., Esmon C. T., Jackson C. M. The conversion of prothrombin to thrombin. I. Characterization of the reaction products formed during the activation of bovine prothrombin. J Biol Chem. 1974 Jan 25;249(2):594–605. [PubMed] [Google Scholar]
  32. Pabinger-Fasching I., Bertina R. M., Lechner K., Niessner H., Korninger C. Protein C deficiency in two Austrian families. Thromb Haemost. 1983 Dec 30;50(4):810–813. [PubMed] [Google Scholar]
  33. Rodeghiero F., Mannucci P. M., Viganò S., Barbui T., Gugliotta L., Cortellaro M., Dini E. Liver dysfunction rather than intravascular coagulation as the main cause of low protein C and antithrombin III in acute leukemia. Blood. 1984 Apr;63(4):965–969. [PubMed] [Google Scholar]
  34. Sala N., Owen W. G., Collen D. A functional assay of protein C in human plasma. Blood. 1984 Mar;63(3):671–675. [PubMed] [Google Scholar]
  35. Samama M., Horellou M. H., Soria J., Conard J., Nicolas G. Successful progressive anticoagulation in a severe protein C deficiency and previous skin necrosis at the initiation of oral anticoagulant treatment. Thromb Haemost. 1984 Feb 28;51(1):132–133. [PubMed] [Google Scholar]
  36. Schwarz H. P., Fischer M., Hopmeier P., Batard M. A., Griffin J. H. Plasma protein S deficiency in familial thrombotic disease. Blood. 1984 Dec;64(6):1297–1300. [PubMed] [Google Scholar]
  37. Seligsohn U., Berger A., Abend M., Rubin L., Attias D., Zivelin A., Rapaport S. I. Homozygous protein C deficiency manifested by massive venous thrombosis in the newborn. N Engl J Med. 1984 Mar 1;310(9):559–562. doi: 10.1056/NEJM198403013100904. [DOI] [PubMed] [Google Scholar]
  38. Sills R. H., Marlar R. A., Montgomery R. R., Deshpande G. N., Humbert J. R. Severe homozygous protein C deficiency. J Pediatr. 1984 Sep;105(3):409–413. doi: 10.1016/s0022-3476(84)80013-x. [DOI] [PubMed] [Google Scholar]
  39. Skogen W. F., Esmon C. T., Cox A. C. Comparison of coagulation factor Xa and des-(1-44)factor Xa in the assembly of prothrombinase. J Biol Chem. 1984 Feb 25;259(4):2306–2310. [PubMed] [Google Scholar]
  40. Stenflo J. A new vitamin K-dependent protein. Purification from bovine plasma and preliminary characterization. J Biol Chem. 1976 Jan 25;251(2):355–363. [PubMed] [Google Scholar]
  41. Stenflo J., Suttie J. W. Vitamin K-dependent formation of gamma-carboxyglutamic acid. Annu Rev Biochem. 1977;46:157–172. doi: 10.1146/annurev.bi.46.070177.001105. [DOI] [PubMed] [Google Scholar]
  42. Suzuki K., Nishioka J., Hashimoto S. Protein C inhibitor. Purification from human plasma and characterization. J Biol Chem. 1983 Jan 10;258(1):163–168. [PubMed] [Google Scholar]
  43. Viganò S., Mannucci P. M., Solinas S., Bottasso B., Mariani G. Decrease in protein C antigen and formation of an abnormal protein soon after starting oral anticoagulant therapy. Br J Haematol. 1984 Jun;57(2):213–220. [PubMed] [Google Scholar]
  44. Viganó S., Mannucci P. M., D'Angelo A., Rumi M. G., Viganó P., Del Ninno E., Cargnel A., Colombo M., Podda M. The significance of protein C antigen in acute and chronic liver biliary disease. Am J Clin Pathol. 1985 Oct;84(4):454–458. doi: 10.1093/ajcp/84.4.454. [DOI] [PubMed] [Google Scholar]
  45. Walker F. J. Regulation of activated protein C by a new protein. A possible function for bovine protein S. J Biol Chem. 1980 Jun 25;255(12):5521–5524. [PubMed] [Google Scholar]
  46. Walker F. J. Regulation of activated protein C by protein S. The role of phospholipid in factor Va inactivation. J Biol Chem. 1981 Nov 10;256(21):11128–11131. [PubMed] [Google Scholar]
  47. Walker F. J., Sexton P. W., Esmon C. T. The inhibition of blood coagulation by activated Protein C through the selective inactivation of activated Factor V. Biochim Biophys Acta. 1979 Dec 7;571(2):333–342. doi: 10.1016/0005-2744(79)90103-7. [DOI] [PubMed] [Google Scholar]
  48. Wessler S., Gitel S. N. Warfarin. From bedside to bench. N Engl J Med. 1984 Sep 6;311(10):645–652. doi: 10.1056/NEJM198409063111007. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES