Protein C Deficiency in a Dutch Family with Thrombotic Disease

Summary

A rabbit antibody against human protein C was used for the quantitative estimation of protein C in plasma. In healthy individuals protein C antigen ranged from 0.65-1.45 U/ml. Plasma protein C antigen was found to be independent of either age or sex. Under influence of oral anticoagulant treatment the protein C antigen concentration decreased to 0.47 U/ml (at low intensity treatment) or 0.33 U/ml (at high intensity treatment). Using normal ranges of protein C and protein C/factor II and protein C/factor X ratios criteria were developed for the assessment of protein C deficiency. In a Dutch family with a history of thrombotic disease two members were found to have an isolated protein C deficiency, while a third one is suspected of protein C deficiency. In one case it was possible to confirm the diagnosis of suspected protein C deficiency during temporary withdrawal of the anticoagulant therapy.

Keywords

Protein C deficiency - Thrombotic disease - Oral anticoagulation

• References

• 1 Stenflo J. A new vitamin-K dependent protein. Purification from bovine plasma and preliminary characterization. J. Biol Chem 1976; 251: 355-363
• 2 Kisiel W, Ericsson LH, Davie EW. Proteolytic activation of protein C from bovine plasma. Biochemistry 1976; 15: 4893-4900
• 3 Kisiel W. Human protein C. Isolation, characterization, and mechanism of activation by ±-thrombin. J Clin Invest 1979; 64: 761-769
• 4 Marlar RA, Kleiss AJ, Griffin JH. Human protein C: inactivation of factor V and VIII in plasma by the activated molecule. Ann NY Acad Sci 1981; 370: 303-310
• 5 Seegers WH, Novoa AE, Henry R, Hassoena H. Relationship of “new” vitamin K dependent protein C and “old” autoprothrombin II-A. Thromb Res 1976; 8: 543-553
• 6 Mammen EF, Thomas WR, Seegers WH. Activation of purified prothrombin to autoprothrombin I or autoprothrombin II (platelet cofactor II) or autoprothrombin II-A. Thrombos Diathes Haemorrh 1960; 5: 218-250
• 7 Fernlund P, Stenflo J, Roepstorff P, Thomsen J. Vitamin K and the biosynthesis of prothrombin. V. Gamma-carboxyglutamic acids, the vitamin K-dependent structures in prothrombin. J Biol Chem 1975; 250: 6125-6133
• 8 Fernlund P, Stenflo J. Amino acid sequence of bovine protein C. In: Suttie JW. (ed.). Vitamin K metabolism and vitamin K dependent proteins. University Park Press; Baltimore: 1979: 84-88
• 9 Kisiel W, Canfield WM, Ericsson LH, Davie EW. Anticoagulant properties of bovine plasma protein C following activation by thrombin. Biochemistry 1977; 16: 5824-5831
• 10 Dahlbäck B, Stenflo J. Inhibitory effect of activated protein C on activation of prothrombin by platelet-bound factor Xa. Eur J Biochem 1980; 107: 331-335
• 11 Esmon CT, Owen WG. Identification of an endothelial cell cofactor for thrombin-catalyzed activation of protein C. Proc Natl Acad Sci USA 1981; 78: 2245-2252
• 12 Seegers WH, Marlar RA, Walz D. Anticoagulant effects of autothrombin-II-A and prothrombin fragment 1. Thromb Res 1978; 13: 233-243
• 13 Zolton RP, Seegers WH. Autoprothrombin II-A: thrombin removal and mechanism of induction of fibrinolysis. Thromb Res 1973; 3: 23-33
• 14 Comp PC, Esmon CT. Evidence for multiple roles for activated protein C in fibrinolysis. In: Mann KG, Taylor FB. (eds.) Regulation of coagulation. Elsevier; New York: 1980: 583-588
• 15 Walker FJ. Regulation of activated protein C by a new protein. A possible function for bovine protein S. J Biol Chem 1980; 255: 5521-5524
• 16 Walker FJ. Regulation of activated protein C by protein S. The role of phospholipid in factor Va inactivation. J Biol Chem 1981; 256: 11128-11131
• 17 Griffin JH, Evatt B, Zimmerman TS, Kleiss AJ, Wideman C. Deficiency of protein C in congenital thrombotic disease. J Clin Invest 1981; 68: 1370-1373
• 18 Bertina RM, Orlando M, Tiedemann-Alderkamp GHJ. Preparation of a human factor VII deficient plasma. Thromb Res 1978; 13: 537-541
• 19 Veltkamp JJ, Drion EF, Loeliger EA. Detection of the carrier state in hereditary coagulation disorders I. Thrombos Diathes Haemorrh 1968; 19: 279-308
• 20 Borchgrevink CF, Pool JG, Stormorken H. A new assay for factor V (proaccelerin-accelerin) using Russell’s viper venom. J Lab Clin Med 1960; 55: 625-632
• 21 Bertina RM, van der Marel-vanNieuwkoop W, Loeliger EA. Spectrophoto-metric assays of prothrombin in plasmas of patients using oral anticoagulants. Thromb Haemostas 1979; 42: 1296-1305
• 22 Bertina RM, Loeliger EA. The potential use of chromogenic assays in the routine monitoring of oral anticoagulant therapy. In: Lijnen HP, Collen D, Verstraete M. (eds.). Synthetic substrates in clinical blood coagulation. Martinus Nijhoff Publishers; The Hague - Boston - London: 1980: 13-23
• 23 Bertina RM, Westhoek-Kuipers MEJ, Alderkamp GHJ. The inhibitor of prothrombin conversion in plasma of patients on oral anticoagulant treatment. Thromb Haemostas 1981; 45: 237-241
• 24 WHO Expert Committee on Biological Standardization. 28th Report. No 610 p 48. Technical Report Series World Health Organization, Geneva 1977
• 25 Mertens K, Bertina RM. Pathways in the activation of human coagulation factor X. Biochem J 1980; 185: 647-658
• 26 Bertina RM, Veltkamp JJ. A genetic variant of factor IX with decreased capacity for Ca²⁺ binding. Br J Haematol 1979; 42: 623-635
• 27 Kazmier FJ, Spiteli JA, Thompson JJ, Owen CA. Effect of oral anticoagulants on factors VII, IX, X and II. Arch Intern Med 1965; 115: 667-673
• 28 Denson KWE. The levels of factors II, VII, IX and X by antibody neutralization techniques in the plasma of patients receiving phenidine therapy. Br J Haematol 1971; 25: 312-315
• 29 Mackie M, Bennett B, Ogston D, Douglas AS. Familial thrombosis: inherited deficiency of antithrombin III. Br Med J 1978; 1: 136-138
• 30 Egeberg O. Inherited antithrombin deficiency causing thrombophilia. Thrombos Diathes Haemorrh 1965; 13: 516-530