New Anticoagulation Targets

• Factor Xa occupies a critical juncture in the coagulation process. It converts prothrombin (Factor II) to thrombin (Factor IIa). Consistent with the observation that coagulation progresses in an amplified manner, one molecule of Factor Xa catalyses the formation of approximately 1000 molecules of thrombin^{15, 16}
• Inhibition of Factor Xa can effectively prevent both platelet-rich arterial thrombi and fibrin-rich venous thrombi⁸⁸

• The only known functions of Factor Xa are to promote coagulation and inflammation. Therefore, in contrast to thrombin inhibition, blocking Factor Xa is less likely to have pleiotropic effects¹⁷
• Selective inhibition of Factor Xa can inhibit thrombin generation while allowing existing thrombin to continue its vital functions in normal haemostasis¹⁷

• Indirect Factor Xa inhibitors, such as fondaparinux, require antithrombin as a cofactor and do not inhibit Factor Xa bound to the prothrombinase complex. In contrast, direct Factor Xa inhibitors directly engage the active centre of the Factor Xa molecule and inhibit both free Factor Xa in plasma and Factor Xa attached to the prothrombinase complex¹⁷

A number of small-molecule, orally administered direct Factor Xa inhibitors are currently in development. These include rivaroxaban, apixaban, betrixaban and a group of as yet unnamed clinical entities (LY517717, YM150 and DU-176b).

Thrombin has a central role in the coagulation pathway. Produced in small amounts in the initiation phase and large amounts in the propagation phase, thrombin is essential for the amplification of coagulation and fibrin formation.^{15, 88}

Parenteral direct thrombin inhibitors currently available for clinical use ― lepirudin, bivalirudin, and argatroban ― are generally reserved for the treatment of patients with heparin-induced thrombocytopenia. These medications are administered parenterally and require individual dosing based on lab monitoring.⁸⁸

The first oral direct thrombin inhibitor available for clinical use was ximelagatran. This medication represented a major advance over existing oral anticoagulants (eg, vitamin K antagonists [VKAs]) because it did not require anticoagulant monitoring or dose adjustments. In clinical trials for venous thromboembolism (VTE) prevention and treatment, ximelagatran was either more effective than or comparable to warfarin. However, safety monitoring revealed liver toxicity in 6% of patients. For this reason, use of the drug was discontinued in 2006.⁸⁸

A second oral direct thrombin inhibitor, dabigatran etexilate, was approved for marketing in the European Union in March 2008 for primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery. Another agent in this class, TGN167, is currently in clinical development.^{88, 132}

In contrast to Factor Xa, thrombin has pleiotropic effects. Activation of protein C that is mediated by thrombin-thrombomodulin inhibits both coagulation and inflammation.¹⁷

The TF-VIIa complex initiates the coagulation process. Exposure of TF during orthopaedic surgery and in certain patients with cancer may contribute to the high rates of VTE in these groups. TF-VIIa therefore presents a possible target for pharmacologic therapy.⁸⁸

Nematode anticoagulant proteins, which inhibit the TF-VIIa/FXa complex, are currently being explored for VTE prophylaxis in orthopaedic surgery.⁸⁸

Theoretically, the advantages of Factor IXa inhibition should be similar to those anticipated for Factor Xa inhibition (ie, blocking an early stage of coagulation amplification, effectiveness in both arterial and venous thromboembolic disease).⁸⁸ Since most of Factor Xa is produced by the intrinsic “tenase,” which includes Factor IXa, targeting Factor IXa may be an effective approach to anticoagulation.^{13, 135} Research in this area, however, is not as advanced as research into Factor Xa inhibition. An oral direct Factor IXa inhibitor, TTP889, is currently in clinical trials for VTE prevention in orthopaedic surgery.⁸⁸

Activated Factors V and VIII serve as cofactors in the prothrombinase and extrinsic “tenase” complexes, respectively. These factors are the targets of the natural anticoagulant activated protein C, a key element of the physiologic thrombomodulatory system. Inhibition by pharmacologic means of one of these factors could potentially block coagulation propagation.^{6, 135}