Expanding the role of coagulation in arterial thrombosis: evidence from animal models using a new factor Xa inhibitor.

Thromb Haemost 2008; 99: 651–652 Anticoagulants represent a mainstay in the current management of arterial thromboembolism. Heparins are recommended for virtually all forms of acute coronary syndromes (1, 2), whereas long-term oral anticoagulation is of proven benefit in the treatment of patients with atrial fibrillation at high risk of stroke, prosthetic mechanical heart valves, chronic heart failure, left ventricular thrombi and systemic lupus erythematosus (3, 4). For the prevention of vascular events in high-risk patients with non-valvular atrial fibrillation, warfarin is superior to aspirin alone and to aspirin plus clopidogrel (5). For the primary and secondary prevention of ischaemic heart disease, warfarin is as effective as aspirin and, added to aspirin, more effective than aspirin alone in reducing major adverse cardiovascular events, although at increased bleeding rates (3, 6). Indirect metaanalyses suggest that the protection by warfarin plus aspirin may not be inferior to that afforded by aspirin plus clopidogrel following an acute coronary syndrome (7). Fibrinolytic drugs, that degrade fibrin and fibrinogen, reduce early vascular mortality after acute myocardial infarction as well as aspirin (8). Finally, at least three hypercoagulable thrombophilic gene variants [prothrombin G20210A, factor V Leiden (G1691A), and plasminogen activator inhibitor type-1 (PAI-1) –6754G/5G], but none of the currently known platelet receptor gene polymorphisms, show a modest but consistent and significant association with the risk of ischaemic heart disease (9). These multiple lines of clinical evidence support a relevant role of coagulation in arterial thromboembolic diseases, equalling or even surpassing the role played by platelets. Currently available anticoagulants include heparins, coumarins, direct thrombin inhibitors, and the indirect factor Xa (FXa) inhibitor, fondaparinux (10). Only coumarins are orally active and thus appropriate for extended therapy, despite their wellknown hurdles. Limits of warfarin include delayed onset of anticoagulant effects, unpredictable dose response, interaction with food and drugs, need for frequent monitoring, difficult standardization of laboratory control, narrow therapeutic window – with its attending haemorrhagic risks – and poor patient compliance (11). Thus, there is a pressing demand for new simple, safe, and effective oral anticoagulants. FXa assembles with cofactor Va and calcium on cellular and platelet surfaces leading to the crucial reaction that converts prothrombin into thrombin. Several inhibitors of FXa are currently under development or investigation (10), including a new group of orally available, competitive, reversible, direct FXa inhibitors: the pyrrolidine-1,2-dicarboxamides (12). Like other direct FXa inhibitors, these agents block both free and surface-bound FXa, bind to the active site of FXa with a 1:1 stoichiometry, and are independent from antithrombin (10). PD0348292 is a small, highly selective inhibitor belonging to this new drug series (13) (Fig. 1).