State-of-the-Art Review: Factor Xa Versus Factor IIa Inhibitors

Abstract

The development of specific inhibitors of blood coagulation enzymes has led to a number of new anticoagulant/antithrombotic agents that could be useful for prophylaxis and/or treatment of thromboembolic disorders. Because thrombin is the central bioregulatory enzyme in hemostasis, blocking of the active site of the enzyme by a fast reaction with an inhibitor may effectively prevent intravascular coagulation as well as other important biological effects of thrombin. For the direct inactivation of thrombin, several classes of compounds have been developed and characterized in vitro and in vivo as potential antithrombotic agents including naturally occurring as well as synthetic thrombin inhibitors such as hirudin, hirulog, arginine (argatroban), and benzamidine (NAPAP) derivatives as well as tripeptide-type inhibitors (efegatran, D-Phe-Pro-Arg-CH₂Cl, boroarginine derivatives). Experimental findings suggest that directly acting thrombin inhibitors may be effective in a wide range of arterial and venous thrombotic events. The important role of factor Xa in the coagulation cascade at the stage of the conversion of extrinsic and intrinsic pathways and the amplification of its procoagulant action by prothrombinase complex formation makes factor Xa a promising target also for antithrombotic drugs. Experimental studies on highly effective and selective factor Xa inhibitors (antistasin, tick anticoagulant peptide, yagin, DX-9065a) showed that inhibition of coagulation at a relatively early stage is a very effective way for the prevention of thrombotic processes. Furthermore, it is assumed that factor Xa inhibitors selectively inhibit thrombus formation without compromising hemostasis. In conclusion, both thrombin and factor Xa inhibitors are promising drugs for the management of thrombotic disorders. However, besides the strong inhibitory potency against the target enzyme, other pharmacological aspects such as pharmacodynamics, pharmacokinetics, and toxic side effects must be included in the evaluation of the potential usefulness of thrombin and factor Xa inhibitors for clinical indications. Key Words: Anticoagulants—Antithrombotics—Factor Xa inhibitors—Thrombin inhibitors.