Inhibition of Thrombin by Antithrombin III and Heparin Cofactor II In Vivo

Summary

The critical role of thrombin in the pathogenesis of venous and arterial thrombosis, and the effectiveness of glycosaminoglycans as antithrombotic drugs are well known. Antithrombin III is a major inhibitor of thrombin and augmentation of its inhibitory actions by heparin is the basis for the clinical uses of heparin. Recent clinical and experimental studies have demonstrated that another glycosaminoglycan, dermatan sulfate, is an effective antithrombotic drug. Dermatan sulfate catalyses the inhibition of thrombin by heparin cofactor II. The concentrations of heparin cofactor II are higher in the plasmas of individuals with congenital antithrombin III deficiency and pregnant women than controls. The role of heparin cofactor II as a physiologic thrombin inhibitor is unknown. Enzyme-linked immunosorbent assays were used to quantify thrombin-heparin cofactor II and thrombin-antithrombin III endogenous to the plasmas of adult antithrombin III-Hamilton deficient subjects, their siblings with normal antithrombin III levels, pregnant women at term and 3 to 5 days after delivery. Both thrombin-antithrombin III and thrombin-heparin cofactor II complexed with vitronectin were detected in all the plasmas. Significantly, the concentrations of thrombin-heparin cofactor II-vitronectin were higher in the plasmas of congenital antithrombin III deficient subjects and in pre- and post-delivery plasmas than those of normal subjects. In addition, the concentrations of thrombin-heparin cofactor II decreased 3 to 5 days after delivery, reflecting the disappearance of the catalytically active dermatan sulfate elaborated by the placenta. Thus, heparin cofactor II normally inactivates thrombin in vivo, with its role increasing in conditions associated with high levels of heparin cofactor II and/or dermatan sulfate.

• References

• 1 Fenton II JW. Thrombin. Ann NY Acad Sei 1986; 485: 5-15
• 2 Teitel JM, Bauer KA, Lau HK, Rosenberg RD. Studies of the prothrombin activation pathway utilizing radioimmunoassays for the F1+2 fragment and thrombin-antithrombin complex. Blood 1982; 59: 1086-1097
• 3 Pelzer H, Schwarz A, Stuber W. Determination of human prothrombin activation fragment 1+2 in plasma with an antibody against a synthetic peptide. Thromb Haemost 1991; 65: 153-159
• 4 Pratt CW, Church FC. Antithrombin: Structure and function. Semin Thromb Haemost 1990; 28: 3-9
• 5 Travis J, Salvesen GS. Human plasma proteinase inhibitors. Ann Rev Biochem 1983; 52: 655-709
• 6 Bjork I, Danielsson A. Antithrombin and related inhibitors of coagulation proteinase. In: Proteinase inhibitors. Barrett AT, Salvesen GS. eds Elsevier; Amsterdam, The Netherlands: 1986. pp 489-513
• 7 Hirsh J, Piovella F, Pini M. Congenital antithrombin III deficiency incidence and clinical features. Am J Med 1989; 87 Suppl (Suppl. 03) B 4S-38S
• 8 Rosenberg RD, Bauer KA. Thrombosis in inherited deficiencies of antithrombin, protein C and protein S. Hum Pathol 1987; 18: 253-262
• 9 Pelzer H, Schwarz A, Heimburger N. Determination of Human thrombinantithrombin III complex in plasma with an enzyme-linked immunosorbent assay. Thromb Haemost 1988; 59: 101-106
• 10 Hoek JA, Sturk A, ten Cate JW, Lamping RG, Berends F, Borm JJ J. Laboratory and clinical evaluations of an assay of thrombin-antithrombin III complexes in plasma. Clin Chem 1988; 34: 2058-2062
• 11 Hoek JA, Nurmohamed MT, ten Cate JW, Büler HR, Knipscheer HC, Hamelynck KJ. et al. Thrombin-antithrombin III complexes in the prediction of deep vein thrombosis following total hip replacement. Thromb Haemost 1989; 62: 1050-1052
• 12 Boneu B, Bes G, Pelzer H, Sié P, Boccalon H. D-Dimers, Thrombin antithrombin III complexes, and prothrombin fragments 1+2: Diagnostic value in clinically suspected deep vein thrombosis. Thromb Haemost 1991; 65: 28-32
• 13 Tollefsen DM, Majerus DW, Blank MK. Heparin cofactor II: Purifications and properties of a heparin inhibitor of thrombin in human plasma. J Biol Chem 1982; 257: 2161-2169
• 14 Buchanan MR, Boneu B, Ofosu FA, Hirsh J. The relative importance of thrombin inhibition and factor Xa inhibition to the antithrombotic effects of heparin. Blood 1985; 65: 198-201
• 15 Lane DA, Ryan K, Ireland H, Curtis JR, Nurmohamed MT, Krediet RT, Roggekamp MC, Stevens P, ten Cate JW. Dermatan sulphate in haemodialysis. Lancet 1992; 339: 334-335
• 16 Agnelli G, Cosmi B, Filippo PD, Ranucci V, Veschi F, Longetti M, Renga C, Barzi F, Gianese F, Luciano L, Rinonapoli E, Nenci G. A randomised, double-blind, placebo-controlled trial of dermatan sulphate for prevention of deep vein thrombosis in hip fracture. Thromb Haemost 1992; 67: 203-208
• 17 Tran TH, Marbet GA. Duckert F: Association of hereditary heparin cofactor II deficiency with thrombosis. Lancet 1985; 2: 413-414
• 18 Sie P, Dupouy D, Pichon J, Boneu B. Constitutional heparin cofactor II deficiency associated with recurrent thrombosis. Lancet 1985; 2: 414-416
• 19 Andrew M, Mitchell LBerry, Paes B, Delorme M, Ofosu FA, Burrows R, Khambalia B. An anticoagulant dermatan sulfate proteoglycan circulates in the pregnant woman and her fetus. J Clin Invest 1992; 89: 321-326
• 20 Miller-Andersson M, Borg H, Andersson LO. Purification of antithrombin III by affinity chromatography. Thromb Res 1974; 5: 439-446
• 21 Preissner KT, Wassmuth R, Muller-Berghaus G. Physiochemical characterization of human S-protein and its function in the blood coagulation system. Biochem J 1985; 231: 349-355
• 22 Shattil SJ, Gunningham M, Hoxie JA. Detection of activated platelets in whole blood using activation-dependent monoclonal antibodies and flow cytometry. Blood 1987; 70: 307-15
• 23 de Boer HC, Groot PG, Bouma BN, Preissner KT. Ternary vitronectin- thrombin-antithrombin III complexes in human plasma. J Biol Chem 1993; 268: 1279-1283
• 24 Demers C, Ginsberg JS, Henderson P, Ofosu FA, Weitz JI, Blajchman MA. Measurement of markers of activated coagulation in antithrombin III deficient subjects. Thromb Haemost 1992; 67: 542-544
• 25 Demers C, Ginsberg JS, Hirsh J, Henderson P, and BlajchmanM. Prevelance of thrombosis in antithrombin-III-deficient individuals: report of a large kindred and literature review. Ann Int Med 1992; 116: 754-761
• 26 Demers C, Henderson P, Blajchman MA, Wells MJ, Mitchell L, Johnston M, Ofosu FA, Fernandez-Rachubinski F, Andrew M, Hirsh J, Ginsberg JS. An antithrombin III assay based on factor Xa inhibition provides a more reliable test to identify congential antithrombin III deficiency than an assay based on thrombin inhibition. Thromb Haemost 1993; 69: 231-235
• 27 Shifman MA, Pizzo SV. The in vivo metabolism of antithrombin III and antithrombin III complexes. J Biol Chem 1982; 257: 3243-3248
• 28 Bauer KA, Goodman TL, Kass BL, Rosenberg RD. Elevated factor Xa activity in the blood of asymptomatic patients with congenital antithrombin deficiency. J Clin Invest 1985; 76: 826-836
• 29 de Boer HC, Preissner KT, Bouma BN, de Groot PG. Binding of vitronectin-thrombin-antithrombin III complex to human endothelial cells is mediated by the heparin binding site of vitronectin. J Biol Chem 1992; 267: 2264-2268
• 30 Gouin-Thibault I, Dewar L, Kulczycky M, Sternback M, Ofosu FA. Factor Xa-antithrombin III complexes in plasma: relationship to prothrombin activation in vivo (submitted for publication).
• 31 Reinthaller A, Mursh-Edlmayer G, and TatraG. Thrombin-antithrombin III complex levels in normal pregnancy with hypertensive disorders and after delivery. Br J Obstet Gynaecol 1990; 97: 506-510
• 32 de Boer K, ten Gate JW, Sturk A, Borm JJ J, Treffers PE. Enhanced thrombin generation in normal and hypertensive pregnancy. Am J Obstet Gynecol 1989; 160: 95-100
• 33 Massauh M, Jatoi A, Gordon EM, Ratnoff OD. Heparin cofactor II activity in plasma during pregnancy and oral contraceptive use. J Lab Clin Med 1989; 114: 697-699
• 34 Knauer DJ, Thompson JA, Cunningham DD. Protease nexins: cell secreted proteins that mediate the binding, internalization and degradation of regulatory serine proteases. J Cell Physiol 1983; 117: 385-396