Inhibition of Thrombin Generation by the Oral Direct Thrombin Inhibitor Ximelagatran in Shed Blood from Healthy Male Subjects

Summary

Ximelagatran, an oral direct thrombin inhibitor, whose active form is melagatran, was studied using a model of thrombin generation in humans. Healthy male volunteers (18 per group) received ximelagatran (60 mg p.o.), dalteparin (120 IU/kg s.c.) or a control (water p.o.). Shed blood, collected after incision of the forearm with standardised bleeding time devices at pre-dose, and at 2, 4 and 10 h post-dosing, was analysed for markers of thrombin generation. Statistically significant reductions (p < 0.05) in levels of prothrombin fragment 1+2 (F1+2) and thrombin-antithrombin complex (TAT) in shed blood were detected at 2 and 4 h post-dosing in both the ximelagatran and dalteparin groups. Shed blood F1+2 and TAT levels had returned to pre-dose levels at 10 h post-dosing. Using a shed blood model, we demonstrate that the reversible thrombin inhibitor melagatran and, therefore, oral administration of ximelagatran, inhibits thrombin generation in humans after acute activation of coagulation.

Keywords

Oral direct thrombin inhibitor - ximelagatran - melagatran - thrombin generation - shed blood

• References

• 1 Becker RC, Bovill EG, Seghatchian MJ, Samama MM. Pathobiology of thrombin in acute coronary syndromes. Am Heart J 1998; 136: S19-S31.
• 2 Fenton II JW, Ofosu FA, Brezniak DV, Hassouna HI. Thrombin and antithrombotics. Semin Thromb Haemost 1998; 24: 87-91.
• 3 Hauptmann J, Stürzebecher J. Synthetic inhibitors of thrombin and factor Xa: From bench to bedside. Thrombosis Research 1999; 93: 203-41.
• 4 Prasa D, Svendsen L, Stürzebecher J. The ability of thrombin inhibitors to reduce the thrombin activity generated in plasma on extrinsic and intrinsic activation. Thromb Haemost 1997; 77: 498-503.
• 5 Eichinger S, Wolzt M, Schneider B, Nieszpaur-Los M, Heinrichs H, Lechner K, Eichler HG, Kyrle PA. Effects of recombinant hirudin (r-hirudin, HBW 023) on coagulation and platelet activation in vivo: Comparison with unfractionated heparin and a low-molecular-weight heparin preparation (Fragmin). Arterioscler Thromb Vasc Biol 1995; 15: 886-92.
• 6 Kyrle PA, Westwick J, Scully MF, Kakkar VV, Lewis GP. Investigation of the interaction of blood platelets with the coagulation system at the site of plug formation in vivo in man – Effect of low dose aspirin. Thromb Haemost 1987; 57: 62-6.
• 7 Weiss HJ, Lages B. Evidence for tissue factor-dependent activation of the classic extrinsic coagulation mechanism in blood obtained from bleeding time wounds. Blood 1988; 71: 629-35.
• 8 Wilcox JN, Smith KM, Schwartz SM, Gordon D. Localization of the tissue factor in the normal vessel wall and in the atherosclerotic plaque. Proc Natl Acad Sci USA 1989; 86: 2839-43.
• 9 Toschi V, Gallo R, Lettino M, Fallon JT, Gertz SD, Fernández-Ortiz A, Chesebro JH, Badimon L, Nemerson Y, Fuster V, Badimon JJ. Tissue factor modulates the thrombogenicity of human atherosclerotic plaques. Circulation 1997; 95: 594-9.
• 10 Badimon JJ, Lettino M, Toschi V, Fuster V, Berrozpe M, Chesebro JH, Badimon L. Local inhibition of tissue factor reduces the thrombogenicity of disrupted human atherosclerotic plaques. Effects of tissue factor pathway inhibitor on plaque thrombogenicity under flow conditions. Circulation 1999; 99: 1780-7.
• 11 Tremoli E, Camera M, Toschi V, Colli S. Tissue factor in atherosclerosis. Atherosclerosis 1999; 144: 273-83.
• 12 von dem PABorne, Koppelman SJ, Bouma BN, Meijers JC. Surface independent factor XI activation by thrombin in the presence of high molecular weight kininogen. Thromb Haemost 1994; 72: 397-402.
• 13 Gustafsson D, Antonsson T, Bylund R, Eriksson U, Gyzander E, Nilsson I, Elg M, Mattsson C, Deinum J, Pehrsson S, Karlsson O, Nilsson A, Sörenson H. Effects of melagatran, a new low-molecular-weight thrombin inhibitor, on thrombin and fibrinolytic enzymes. Thromb Haemost 1998; 79: 110-8.
• 14 Eriksson UG, Johansson L, Frison L, Bredberg U, Gustafsson D. Single and repeated oral dosing of H 376/95, a prodrug to the direct thrombin inhibitor melagatran, to young healthy male subjects. Blood (abstract). 1999 94. 10 (Suppl. 1 of 2): 26a.
• 15 Gustafsson D, Nyström J-E, Carlsson S, Bredberg U, Eriksson U, Gyzander E, Elg M, Antonsson T, Hoffman K-J, Ungell A-L, Sörensen H, Någård S, Abrahamsson A, Bylund R. The direct thrombin inhibitor melagatran and its oral prodrug H 376/95: Intestinal absorption properties, biochemical and pharmacodynamic effects. Thrombosis Research 2001; 101: 171-81.
• 16 Ernofsson M, Strekerud F, Toss H, Abildgaard U, Wallentin L, Siegbahn A. Low molecular weight heparin reduces the generation and activity of thrombin in unstable coronary artery disease. Thromb Haemost 1998; 79: 491-4.
• 17 Wolzt M, Eder M, Weltermann A, Entlicher J, Eichler HG, Kyrle PA. Comparison of the effects of different low molecular weight heparins on the hemostatic system activation in vivo in man. Thromb Haemost 1997; 78: 876-9.
• 18 Kyrle PA, Brockmeier J, Weltermann A, Eichinger S, Speiser W, Lechner K, Eichler HG. Inhibition rather than enhancement of hemostatic system activation during initiation of oral anticoagulant treatment. Thromb Haemost 1997; 77: 685-9.
• 19 Szczeklik A, Musial J, Undas A, Gajewski P, Góra P, Swadzba J, Jankowski M. Inhibition of thrombin generation by simvastatin and lack of additive effects of aspirin in patients with marked hypercholesterolemia. J Am Coll Cardiol 1999; 33: 1286-93.
• 20 Deinum J, Elg S. The effect of melagatran on the binding of thrombin to antithrombin studied by plasmon resonance. Haemostasis 2000; 30 (Suppl. 01) 165.
• 21 Swedenborg J. The mechanisms of action of alphaand beta-isoforms of antithrombin. Blood Coagul Fibrinolysis 1998; 09 (Suppl. 03) S7-S10.
• 22 Menschik-Lundin A, Nylander S, Mattsson C, Dahlbäck B, Berntsdotter A. Inhibition of protein C activation by anticoagulant compounds with different modes of action. Haemostasis 2000; 30 (Suppl. 01) 164.
• 23 Eriksson BI, Lindbratt S, Kälebo P, Bylock A, Frison L, Welin L, Dahl O, Gustafsson D. Methro II: Dose-response study of the novel oral, direct thrombin inhibitor, H 376/95 and its subcutaneous formulation melagatran, compared with dalteparin as thromboembolic prophylaxis after total hip or total knee replacement. Haemostasis 2000; 30 (Suppl. 01) 20-1.