RSS-Feed abonnieren
DOI: 10.1055/s-0038-1645685
Effect of Protein C and Activated Protein C on Coagulation and Fibrinolysis in Normal Human Subjects
Publikationsverlauf
Received 21. Juni 1989
Accepted after revision 01. November 1989
Publikationsdatum:
02. Juli 2018 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/199001/lookinside/thumbnails/10-1055-s-0038-1645685-1.jpg)
Summary
Although protein C (PC) and activated protein C (APC) have been postulated to be useful for treating patients with thrombosis, their critical effect remains to be studied in human subjects. To examine whether purified PC or APC are useful for treating patients with thrombosis without showing any adverse effect, wc studied effects on coagulation and fibrinolysis in normal human subjects.
When highly purified human PC was administered intravenously to healthy subjects, plasma levels of immunoreactive PC decreased with a half-life of 10.9 h. Intravenously administered APC decreased with a half-life of 23 min as measured by prolongation of activated partial thromboplastin time (APTT). However, 1.7 h was obtained for the plasma half-life of APC when it was measured immunologically. These findings suggested that a significant fraction of the administered APC was rapidly inhibited by plasma inhibitor. Upon administration of APC, APTT was prolonged and plasma levels of clotting factor VIII (FVIII) decreased transiently as measured by clotting assay. However, when determined by a chromogenic assay method in which 120-fold diluted plasma samples were used, plasma levels of FVIII remained unchanged. Plasma levels of F-V did not decrease after APC administration. These findings suggested that prolongation of APTT and apparent decrease in plasma F-VIII clotting activity might be due to the in vitro-effect of APC present in plasma samples used. Diurnal fluctuation of plasminogen activator inhibitor in normal subjects was not affected by administration of APC.
Thus, PC or APC seems to function selectively at the site of thrombin-formation without lowering plasma levels of coagulation factors.
-
References
- 1 Esmon CT. The Regulation of natural anticoagulant pathways. Science 1987; 235: 1348-51
- 2 Esmon CT. Protein C: Biochemistry, physiology and clinical implications. Blood 1983; 62: 1151-1158
- 3 Walker FJ, Sexton PW, Esmon CT. The inhibition of blood coagulation by activated protein C through selective inactivation of activated factor V. Biochim Biophys Acta 1979; 571: 333-342
- 4 Sakata Y, Curriden S, Lawrence D, Griffin JH, Luskutoff DJ. Activated protein C stimulates the fibrinolytic activity of cultured endothelial cells and decreases antiactivator activity. Proc Natl Acad Sci 1985; 82: 1121-1125
- 5 Griffin JH, Evatt B, Zimmerman TS, Kleiss AJ. Deficiency of protein C in congenital thrombotic disease. J Clin Invest 1981; 68: 1370-1373
- 6 Griffin JH, Mosher DF, Zimmerman TS, Kleiss AJ. Protein C, an antithrombotic protein, is reduced in hospitalized patients with intravascular coagulation. Blood 1982; 60: 261-264
- 7 Esmon CT, Taylor Jr FB, Hinshaw LB, Chang A, Comp PC, Ferrell G, Esmon NL. Protein C, isolation and potential use in prevention of thrombosis. Joint IABS/CSL Symposium on Blood Fractionation including Coagulation Factors (Melbourne, Australia, 1986). Dev. Biol. Standard. S. Larger 1987 67. 51-57
- 8 Taylor Jr FB, Chang A, Esmon CT, D’Anglo A, Vigano-Angelo S, Blick KE. Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon. J Clin Invest 1987; 79: 918-925
- 9 Mannucci PM, Vigano S. Protein C concentrates for therapeutic use. Lancet 1983; 1: 875
- 10 Comp PC, Nixon RR, Esmon CT. Determination of functional levels of protein C, an antithrombotic protein, using thrombin-throm-bomodulin complex. Blood 1984; 63: 115-121
- 11 Martinoli JL, Stocker K. Fast functional protein C assay using Protac, a novel protein C activator. Thromb Res 1986; 43: 253-264
- 12 Shimamoto M, Yoshimura T, Kimura N. Determination of protein C in human plasma by homogeneous enzyme immunoassay with a centrifuge analyzer. Clin Chem 1988; 34: 1834-1838
- 13 Kappela R. Das Verhalten von Faktor V in Serum unter normalen und pathologischen Bedingungen. Z Klin Med 1955; 153: 103-113
- 14 Hardisty RM, Macpherson JC. A one stage factor VIII (antihemophilic globulin) assay and its use on venous and capillary plasma. Thromb Dialh Haemorrh 1962; 7: 215-229
- 15 Rosen S, Friberger P, Andersson M, Vinazzer H. A new chromogenic assay for determination of human factor VIII :C activity. In: Standardization of Coagulation Assays: An Overview Triplett DA. (ed). College of American Pathologist. North Skokie, 111: 1982
- 16 Eriksson E, Randy M, Gyzander E, Riseberg B. Determination of plasminogen activator inhibitor in plasma using t-PA and a chromogenic single-point poly-D-lysine stimulated assay. Thromb Res 1988; 50: 91-101
- 17 Declerck PJ, Alessi MC, Verstreken M, Kruitof EK O, Juhan-Vague I, Collen D. Measurement of plasminogen activator inhibitor 1 (PAI-1) in biological fluids, with a murine monoclonal antibody based enzyme-linked immunosorbent assay. Blood 1988; 71: 220-225
- 18 Harpel PC. α2-plasmin inhibitor and -macroglobulin and -plasmin complexes in plasma. J Clin Invest 1981; 68: 46-55
- 19 Verheijen JH, Mullaart E, Chang GT G, Kluft C, Wijngaards G. A simple sensitive spectrophotometric assay for extensive (tissue-type) plasminogen activator applicable to measurement in plasma. Thromb Haemostas 1982; 48: 266-269
- 20 Collen D, Schetz J, Cock FD, Holmer E, Verstraete M. Metabolism of antithrombin III (heparin cofactor) in man: effects of venous thrombosis and of heparin administration. Eur J Clin Invest 1977; 7: 27-35
- 21 Weber K, Pringle JR, Osborn M. Measurement of melecular weight by electrophoresis on SDS-acrylamide gel. Meth Enzymol 1972; 26: 3-27
- 22 Stern DM, Nawroth PP, Harris KW, Esmon CT. Cultured bovine aortic endothelial cells promote activated protein C-protein S-medi-ated inactivation of factor Va. J Biol Chem 1986; 261: 713-718
- 23 Blauhut B, Kramar H, Vinazzer H, Bergmann H. Substitution of antithrombin III in shock and DIC; A randomized study. Thromb Res 1985; 39: 81-85
- 24 Comp PC, Esmon CT. Generation of fibrinolytic activity by infusion of activated protein C into dogs. J Clin Invest 1984; 68: 1221-1228
- 25 Colucci M, Stassen JM, Collen D. Influence of protein C activation on blood coagulation and fibrinolysis in squirrel monkeys. J Clin Invest 1984; 74: 200-204
- 26 Okajima K, Koga S, Nakagaki T, Funatsu A, Okabe H, Takatsuki K. Role of protein C in endotoxin-induced release of plasminogen activator inhibitor from endothelial cell. Acta Haematol Jpn 1989: 52 (in press)
- 27 Heeb MJ, Espana F, Griffin JH. Inhibition and complexation of activated protein C by two major inhibitors in plasma. Blood 1989; 73: 446-454