Novel Direct Factor IIa and Xa Inhibitors: Mechanisms of Action and Preclinical Studies

Spyridon      Deftereos; Nikolaos      Anatoliotakis; Georgios      Giannopoulos; Andreas      Kaoukis; Maria      Mavri; Vlasios      Pyrgakis; Christodoulos      Stefanadis

Abstract

The need to overcome certain limitations of the existing anticoagulant agents (heparin, LMWH and VKAs) and to achieve more convenient long-term anticoagulation has fueled the quest for the “ideal anticoagulant”, an agent that would exert at least similar antithrombotic effects with a substantially improved pharmacologic profile and significantly less bleeding complications. The major disadvantages of the traditional agents were the narrow therapeutic window with serious drug and food interactions and the need for regular blood monitoring. Coagulation factors IIa and Xa have proved the most attractive pharmacologic targets due to their key role in the coagulation process and the opportunity of blocking thrombin generation before the level of thrombin production that results in amplification of the anticoagulant effect while preserving some of thrombin hemostatic effect. This review summarizes the mechanism of action of some of the most promising novel oral direct factor IIa and Xa inhibitors with a focus on published preclinical trials that led to their clinical development.

Keywords: Factor IIa inhibitors, factor Xa inhibitors, long-term anticoagulation, novel anticoagulants, oral anticoagulants, preclinical studies, Dabigatran, Rivaroxaban, Betrixaban, Apixaban, Eribaxaban