o fi brin and fi brin forms a mesh that, in conjunction with the platelets, plugs the break in the vessel wall. Thrombin also catalyzes the activation of Factor XIII, consequently stabilizing the fi brin network by forming crosslinks. Conventional therapies act on multiple targets within the coagulation cascade. VKAs inhibit the vitamin K dependent�?carboxylation of the clotting factors prothrombin Brivanib BMS-540215 and Factors VII, IX and X.
UFH and LMWHs potentiate the inhibitory action of antithrombin on thrombin Table 1 Limitations of current anticoagulants Anticoagulant Limitations Consequences UFH Parenteral mode of administration Inconvenient for long term use Unpredictable anticoagulant effect due to unspecifi c binding Regular monitoring of aPTT required Risk of HIT Monitoring WZ3146 of platelet count required LMWH Parenteral mode of administration Inconvenient and expensive for long term use Risk of HIT Monitoring of platelet count required VKAs Unpredictable anticoagulant effect Slow onset of action and narrow therapeutic window Regular monitoring and dose adjustment required to ensure patients stay within target INR Food and drug interactions Risk of adverse events Fondaparinux Parenteral mode of administration Inconvenient and expensive for long term use Abbreviations: UFH, unfractionated heparin, LMWH, low molecular weight heparin, VKAs, vitamin K antagonists, aPTT, activated partial thromboplastin time, HIT, heparin induced thrombocytopenia, INR, international normalized ratio. Vascular Health and Risk Management 2008:4 1375 Novel oral antithrombotics and FXa, and also induce the release of TF pathway inhibitor from endothelial cells, further enhancing their anticoagulant activity.
The unpredictable anticoagulation patterns sometimes observed with VKAs and UFH could in part be explained by their action on multiple factors, because each factor targeted has a different half life. Furthermore, thrombin formation is individualized due to genetic factors that are still not fully understood. In addition, conventional therapies are unable to antagonize the effects of thrombin bound to the clot, even though clot bound thrombin retains enzymatic activity. Because thrombin potentiates its own generation via feedback stimulation of FV, FVIII, and FIX, this creates the potential for therapeutic failure.
In an attempt to render the effects of anticoagulants more predictable than the VKAs and UFH, recent research efforts have focused primarily on the direct inhibition of a single coagulation factor, namely thrombin and FXa two serine proteases with key functions in the coagulation cascade. Thrombin is a procoagulant but also plays an important role in anticoagulation and anti infl ammation via thrombin thrombomodulin mediated activation of protein C. Thrombin also promotes infl ammation and cellular proliferation. The early direct thrombin inhibitors bivalirudin and argatroban, which provided proof of concept for direct thrombin inhibition, are still in use today. However, due to their specific pharmacokinetic and pharmacodynamic properties, they are used only in specifi c patient populations, eg in patients undergoing percutaneous coronary intervention or in patients with HIT. Ximelegatran was the fi rst oral DTI developed and was a prodrug of the active site directed thrombin inhibitor, melagatran. Ximelagatran was shown to be effective for the prevention and treatment of VTE in several phase II and phase III clinical trials: METHRO III, EXPRESS, EXULT A an