Comparison of the Anticoagulant and Antithrombotic Effects of Synthetic Thrombin and Factor Xa Inhibitors

Summary

The anticoagulant effect of selected synthetic inhibitors of thrombin and factor Xa was studied in vitro in commonly used clotting assays. The concentrations of the compounds doubling the clotting time in the various assays were mainly dependent on their thrombin inhibitory activity. Factor Xa inhibitors were somewhat more effective in prolonging the prothrombin time compared to the activated partial thromboplastin time, whereas the opposite was true of thrombin inhibitors.

In vivo, in a venous stasis thrombosis model and a thromboplastin-induced microthrombosis model in rats the thrombin inhibitors were effective antithrombotically whereas factor Xa inhibitors of numerically similar IQ value for the respective enzyme were not effective at equimolar dosage

The results are discussed in the light of the different prelequisiles and conditions for inhibition of thrombin and factor Xa in the course of blood clotting.

• References

• 1 Kikumoto R, Tamao Y, Tezuka T, Tonomura S, Hara H, Ninomiya K, Hijikata A, Okamoto S. Selective inhibition of thrombin by (2R,4R)-4-methyl-l-[N²-[(3-methyl-l,2,3,4,-tetrahydro-8-quinolinyl)sulfonyl]-L-arginyl]-2-piperidine-carboxylic acid. Biochemistry 1984; 23: 85-90
• 2 Stürzebecher J, Markwardt F, Voigt B, Wagner G, Walsmann P. Cyclic amides of Nα-arylsulfonylaminoacylated 4-amidinophenylalanine - tight binding inhibitors of thrombin. Thromb Res 1983; 29: 635-642
• 3 Hauptmann J, Markwardt F, Walsmann P. Synthetic inhibitors of serine proteinases. XVI. Influence of 3- and 4-amidinobenzyl derivatives on the formation and action of thrombin. Thromb Res 1978 12. 735-744
• 4 Tidwell RR, Webster WP, Shaver SR, Geratz JD. Strategies for anticoagulation with synthetic protease inhibitors. Xa inhibitors versus thrombin inhibitors. Thromb Res 1980 19. 339-349
• 5 Yin ET, Wessler S. Heparin accelerated inhibition of activated factor X by its natural plasma inhibitor. Biochim Biophys Acta 1970; 201: 387-390
• 6 Wessler S. Mini-dose heparin. Thrombos Diathes haemorrh 1975; 34: 718-726
• 7 Stürzebecher J, Stiirzebecher U, Vieweg H, Wagner G, Hauptmann J, Markwardt F. Synthetic inhibitors of factor Xa and thrombin. Comparison of their anticoagulant efficiency. Thromb Res 1989 54. 242-252
• 8 Hauptmann J, Kaiser B, Markwardt F, Nowak G. Anticoagulant and antithrombotic action of novel specific inhibitors of thrombin. Thromb Haemostas 1980; 43: 118-123
• 9 Markwardt F, Nowak G, Hoffmann J. Comparative study on thrombin inhibitors in experimental microthrombosis. Thromb Haemostas 1983; 49: 235-237
• 10 Kaiser B, Markwardt F. Antithrombotic and haemorrhagic effects of synthetic and naturally occurring thrombin inhibitors. Thromb Res 1986; 43: 613-620
• 11 Aronson DL. In vivo consumption of prothrombin during clot formation: An “all or none” phenomenon. Thromb Res 1985; 37: 693-695
• 12 Tracy PB. Regulation of thrombin generation at all cell surfaces. Semin Thromb Haemostas 1988; 14: 227-233
• 13 Jesty J. Analysis of the generation and inhibition of activated coagulation factor X in pure systems and in human plasma. J Biol Chem 1986; 261: 8695-8702
• 14 Ofosu FA, Sie P, Modi GJ, Fernandez F, Buchanan MR, Blajchman MA, Boneu B, Hirsh J. The inhibition of thrombin-dependent positive feedback-reactions is critical to the expression of the anticoagulant effect of heparin. Biochem J 1987; 243: 579-588
• 15 Béguin S, Lindhout T, Hemker HC. The mode of action of heparin in plasma. Thromb Haemostas 1988; 60: 457-462
• 16 Ofosu FA, Blajchman MA, Modi GJ, Smith LM, Buchanan MR, Hirsh J. The importance of thrombin inhibition for the expression of the anticoagulant activities of heparin, dermatan sulphate, low molecular weight heparin and pentosan polysulphate. Br J Haematol 1985; 60: 695-704
• 17 Pieters J, Lindhout T. The limited importance of factor Xa inhibition to the anticoagulant property of heparin in thromboplastin-activated plasma. Blood 1988; 72: 2048-2052
• 18 Ockelford PA, Carter CJ, Mitchell L, Hirsh J. Discordance between the anti-Xa activity and the antithrombotic activity of an ultra-low molecular weight heparin fraction. Thromb Res 1982; 28: 401-409
• 19 Buchanan MR, Boneu B, Ofosu F, Hirsh J. The relative importance of thrombin inhibition and factor Xa inhibition for the antithrombotic effects of heparin. Blood 1985; 65: 198-201
• 20 Hemker HC, Willems GM, Béguin SA. A computer assisted method to obtain the prothrombin activation velocity in whole plasma independent of thrombin decay processes. Thromb Haemostas 1986; 56: 9-17
• 21 Bode AP, Miller DT. The use of thrombin inhibitors and aprotinin in the preservation of platelets stored for transfusion. J Lab Clin Med 1989; 113: 753-758