Protein C Levels in Disseminated Intravascular Coagulation and Thrombotic Thrombocytopenic Purpura: Its Correlation with Other Coagulation Parameters

Summary

Protein C was measured by means of enzyme-linked immunosorbent assay (ELISA) in plasmas from 58 normal subjects, 39 patients with disseminated intravascular coagulation (DIC) and 5 patients with thrombotic thrombocytopenic purpura (TTP). Protein C levels ranged from 69.7 to 163.6% (95% confidence limits) in normal subjects. In patients with DIC, protein C concentrations were significantly decreased, with a geometric mean value of 42.1%. Protein C concentration was positively correlated with plasma prothrombin, antithrombin III and serum pseudocholinesterase, and was negatively correlated with von Willebrand factor antigen (vWF: Ag) and vWF: Ag/factor VIII ratio. These findings suggest that low protein C concentrations in DIC mean a consumption of protein C probably due to its activation by thrombin and/or impaired liver synthetic function. In patients with TTP, protein C levels were normal with a geometric mean value of 116.7%, indicating that the pathophysiology of TTP is quite different from that of DIC.

Keywords

Protein C - Disseminated intravascular coagulation - Thrombotic thrombocytopenic purpura - Enzyme-linked immunosorbent assay (ELISA) - von Willebrand factor

• 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 plasma protein C. Isolation, characterization and mechanism of activation by α-thrombin. J Clin Invest 1979; 64: 761-769
• 4 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 1961; 05: 218-249
• 5 Esmon NT, Owen WG, Esmon CT. Isolation of a membrane-bound cofactor for thrombin-catalyzed activation of protein C. J Biol Chem 1982; 257: 859-864
• 6 Kisiel W, Canfield WM, Ericsson LH, Davie EW. Anticoagulant properties of bovine plasma protein C following activation by thrombin. Biochemistry 1977; 16: 5824-5831
• 7 Marlar RA, Kleiss AJ, Griffin JH. Human protein C: Inactivation of factors V and VIII in plasma by the activated molecule. Ann NY Acad Sci 1981; 370: 303-310
• 8 Marlar RA, Kleiss AJ, Griffin JH. Mechanism of action of human activated protein C, a thrombin-dependent anticoagulant enzyme. Blood 1982; 59: 1067-1072
• 9 Seegers WH, McCoy LE, Groben HD, Sakuragawa N, Agrawal BBL. Purification and some properties of autoprothrombin II-A. An anticoagulant perhaps also related to fibrinolysis. Thromb Res 1972; 01: 443-460
• 10 Comp PC, Esmon CT. Generation of fibrinolytic activity by infusion of activated protein C into dogs. J Clin Invest 1981; 68: 1221-1228
• 11 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
• 12 Bertina RM, Broekmans AW, van der Linden IK, Mertens K. Protein C deficiency in a Dutch family with thrombotic disease. Thromb Haemostas 1982; 48: 01-05
• 13 Broekmans AW, Veltkamp JJ, Bertina RM. Congenital protein C deficiency and venous thromboembolism. A study of three Dutch families. N Engl J Med 1983; 309: 340-344
• 14 Bertina RM, Broekmans AW, Krommenhoek-van EsC, van Wijngaarden A. The use of a functional and immunologic assay for plasma protein C in the study of the heterogeneity of congenital protein C deficiency. Thromb Haemostas 1984; 51: 01-05
• 15 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
• 16 Mannucci PM, Vigano S. Deficiencies of protein C, an inhibitor of blood coagulation. Lancet 1982; 02: 463-467
• 17 Francis RB, Thomas W. Behaviour of protein C inhibitor in intravascular coagulation and liver disease. Thromb Haemostas 1984; 52: 71-74
• 18 Kobayashi N, Maekawa T, Takada M, Tanaka H, Gonmori H. Criteria for diagnosis of DIC based on the analysis of clinical and laboratory findings in 345 DIC patients collected by the research committee on DIC in Japan. Bibl Haematol 1983; 49: 265-275
• 19 Biggs R. Human blood coagulation, haemostasis and thrombosis. Blackwell Scientific; Oxford: 1976: 657-750
• 20 Laurell CB. Electroimmunoassay. Scand J Clin Lab Invest 1977; 29 (Suppl. 124) 21-37
• 21 Takahashi H. Studies on the pathophysiology and treatment of von Willebrand’s disease. I. Spectrum of von Willebrand’s disease in Niigata. Acta Haematol Jpn 1981; 44: 154-164
• 22 Ødegard OR, Fagerhol MK. Heparin cofactor activity and antithrombin III concentration in plasma related to age and sex. Scand J Haematol 1976; 17: 258-262
• 23 Abildgaard U, Lie M, Ødegard OR. Antithrombin (heparin cofactor) assay with “new” chromogenic substrates (S-2238 and Chromozym TH). Thromb Res 1977; 11: 549-553
• 24 Friberger P, Knos M, Gustavsson S, Aurell L, Claeson G. Methods for determination of plasmin, antiplasmin and plasminogen by means of substrate S-2251. Haemostasis 1978; 07: 138-145
• 25 Matsuda T, Ogawara M, Miura R, Seki T, Matsumoto T, Teramura Y, Nakamura K. Selective determination of α₀₂-plasmin inhibitor activity in plasma using chromogenic substrate. Thromb Res 1984; 33: 379-388
• 26 Vigano S, Mannucci PM, 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; 57: 213-220
• 27 Vellenga E, Mulder NH. Normal levels of antithrombin III in acute leukemia complicated by coagulopathy. Acta Haematol 1980; 63: 336-338
• 28 Sié P, Letrenne E, Caranobe C, Genestal M, Cathala B, Boneu B. Factor II related antigen and antithrombin III as indicators of liver failure in consumption coagulopathy. Thromb Haemostas 1982; 47: 218-220
• 29 Rodeghiero F, Mannucci PM, Vigano 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; 63: 965-969
• 30 Denson KWE. The ratio of factor VIII-related antigen and factor VIII biological activity as an index of hypercoagulability and intravascular clotting. Thromb Res 1977; 10: 107-119
• 31 Emekli NB, Ultin ON. The protective effect of autoprothrombin II anticoagulant on experimental DIC formed elements. Haematologica 1980; 65: 644-651
• 32 Suzuki K, Nishioka J, Hashimoto S. Protein C inhibitor: Purification from human plasma and characterization. J Biol Chem 1983; 258: 163-168
• 33 Suzuki K, Nishioka J, Kusumoto H, Hashimoto S. Mechanism of inhibition of activated protein C by protein C inhibitor. J Biochem 1984; 95: 187-195
• 34 Bauer KA, Kass BL, Beeler DL, Rosenberg RD. Detection of protein C activation in humans. J Clin Invest 1984; 74: 2033-2041
• 35 Ridolfi RL, Bell WR. Thrombotic thrombocytopenic purpura. Report of 25 cases and review of the literature. Medicine 1981; 60: 413-428
• 36 Machin SJ. Thrombotic thrombocytopenic purpura. Br J Haematol 1984; 56: 191-197
• 37 Remuzzi G, Misiani R, Mecca G, de Gaetano G, Donati MB. Thrombotic thrombocytopenic purpura – A deficiency of plasma factors regulating platelet-vessel-wall interaction?. N Engl J Med 1978; 299: 311
• 38 Chen YC, McLeod B, Hall ER, Wu KK. Accelerated prostacyclin degradation in thrombotic thrombocytopenic purpura. Lancet 1981; 02: 267-269
• 39 Lian ECY, Harkness DR, Byrnes JJ, Wallach H, Hunez R. Presence of a platelet aggregating factor in the plasma of patients with thrombotic thrombocytopenic purpura (TTP) and its inhibition by normal plasma. Blood 1979; 55: 333-338
• 40 Lian ECY, Mui PTK, Siddiqui FA, Chiu AYY, Shiu LLS. Inhibition of platelet-aggregating activity in thrombotic thrombocytopenic purpura plasma by normal adult immunoglobulin G. J Clin Invest 1984; 73: 548-555
• 41 Moake JL, Rudy CK, Trall JH, Weinstein MJ, Colannino NM, Azocare J, Seder RH, Hong SL, Deykin D. Unusually large plasma factor VIII: von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura. N Engl J Med 1982; 307: 1432-1435
• 42 Jaffe EA, Nachman RL, Merskey C. Thrombotic thrombocytopenic purpura – a coagulation parameter in twelve patients. Blood 1973; 42: 499-507
• 43 Cuttner J. Thrombotic thrombocytopenic purpura: A ten-year experience. Blood 1980; 56: 302-306