Thrombin inhibitors antithrombotic effect

Contraindications are similar to those of other antithrombotic drugs, and hemorrhage is the most common and serious adverse effect. For all agents in this class, a CBC should be obtained at baseline and periodically thereafter to detect potential bleeding. There are no known agents that reverse the activity of direct thrombin inhibitors. 

Protein C exerts an antithrombotic effect by inhibiting Factors Va and Villa. In vitro data indicate that it has indirect prohbri-nolytic activity through its abhity to inhibit plasminogen activator inhibitor-1 (PAI-1) and to hmit production of activated throm-bin-activatable-hbrinolysis inhibitor. In vitro data also indicate that Activated Protein C may exert an anti-inflammatory effect by inhibiting human tumor necrosis factor production by monocytes, by blocking leukocyte adhesion to selectins, and by hmiting thrombin-induced inflammatory responses within the microvascular endothehum. 

The indirect thrombin inhibitors are so-named because their antithrombotic effect is exerted by their interaction with a separate protein, antithrombin. Unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), and the... 

Hauptmann J, Kaiser B, Vowak G, Struzebecher J, Markwardt F. Comparison of the anticoagulant and antithrombotic effects of synthetic thrombin and factor Xa inhibitors. Throm Haemostas 1990 63 220-223. 

Elg M, Gustafsson D, Carlsson S. Antithrombotic effects and bleeding time of thrombin inhibitors and warfarin in the rat. Thromb Res 1999 94 187-197. 

Sarich TC, Osende Jl, Eriksson UG, et al, Acute antithrombotic effects of ximelagatran, an oral direct thrombin inhibitor, and r-hirudin in a human ex vivo model of arterial thrombosis, J Thromb Haemost 2003 1 999— 1004. 

Morishima Y Tanabe K, Terada Y et al. Antithrombotic and hemorrhagic effects of DX-9065a, a direct and selective factor Xa inhibitor comparison with a direct thrombin inhibitor and antithrombin Ill-dependent anticoagulants. Thromb Haemost 1997 78 1366-1371. 

Antithrombotic effects Decreased matrix metalloproteinases Increased tissue inhibitor of metalloproteinase 1 Increased collagen and fewer inflammatory cells in atherosclerotic plaque Reduced tissue factor expression and thrombin generation... 

Aronson DL, Thomas DP (1985) Experimental studies on venous thrombosis effect of coagulants, procoagulants and vessel contusion. Thromb Haemost 54 866-870 Biemond BJ, Friedeiich PW, Levi M et al. (1996) Comparison of sustained antithrombotic effects of inhibitors of thrombin and factor Xa in experimental thrombosis. Circulation 93 153-160... 

In contrast to thrombin inhibitors, the fector Xa inhibitors are devoid of bleeding effects even at dosages much higher than supra-therapeutic levels, which in the case of heparin are responsible for bleeding. Thus, a dissociation between the bleeding and antithrombotic responses is clearly evident for both DX-9065a and pentasaccharide. 

F(ab )2 (0.4mg/kg) with the thrombin inhibitor efegatran (2h infusion at 0.25mg/kg/h) gave an antithrombotic effect equivalent to that obtained using 7E3 F(ab )2 alone (0.8mg/kg), but with a smaller increase in bleeding time [144],... 

The compounds potently inhibit factor Xa in vitro with reversible binding kinetics and are able to inhibit not only free but also prothrombinase-bound factor Xa (Ki 41 nM, 0.1 I nM, and 0,5 nM, respectively) (58-60), In contrast, no direct effect on platelet aggregation has been described (60-62), Antithrombotic activity in arterial and venous thrombosis models has been demonstrated and it has a reduced effect on hemorrhage in comparison to standard therapy (58,60,63). Factor Xa inhibitors are able to reduce the endogenous thrombin potential in platelet-poor as well as in platelet-rich plasma (64,65). Thus, thrombin generation seems to be a suitable biomarker for clinical evaluation and has been evaluated in phase I studies (66,67). 

Thrombin and factor Xa are prominent players in the blood clotting cascade. They are, therefore, important targets for the development of new anticoagulant/antithrombotic drugs. Trypsin is an enzyme excreted by the pancreas for helping in digestion, and has classically been used as a model enzyme for the whole serine protease family. Thus, in order to minimize side-effects of thrombin/factorXa inhibitors, and to enhance their bioavailability, potential drugs should exhibit selectivity towards thrombin/factorXa with respect to trypsin. 

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