stered by subcutaneous injection, and accumulation can occur in patients with renal impairment. VKAs have been in use in humans for more than 50 years and are currently the only oral anticoagulants available. The utility of VKAs is limited by the diffi culty of managing them, the requirement of frequent monitoring and the necessity for dose adjustment to limit BMY 7378 the adverse consequences of a narrow therapeutic window, multiple food and drug interactions, and variable pharmacology. These qualities, in addition to 1374 Vascular Health and Risk Management 2008:4 Lassen and Laux the bleeding risk and other adverse effects, may contribute to the frequent underuse of warfarin, especially in elderly patients. In addition, VKAs have a slow onset of action.
This can be a particular problem in VTE treatment, when the patient is at immediate risk of thrombus growth. In this situation, bridging ABT-751 therapy initiated with parenteral anticoagulants with a fast onset of action is necessary. Fondaparinux, approved for use in the US in 2001 and Europe in 2002, has been shown to be relatively safe and effective in a variety of indications. However, like the heparins, it requires parenteral administration, which can be inconvenient when long term use is necessary. Moreover, fondaparinux can also accumulate in patients with renal impairment due to renal elimination kinetics. Clearly, there is an unmet need for a convenient, safe antithrombotic agent that can be administered orally and does not require frequent monitoring or dose adjustment.
Current focus of antithrombotic development The rationale behind the development of antithrombotics is based on an understanding of the coagulation cascade. The coagulation cascade can be initiated via either the intrinsic or extrinsic pathways. Initiation of the intrinsic coagulation cascade occurs when prekallikrein, high molecular weight kininogen, Factor XI, and Factor XII are exposed to a negatively charged surface, eg, phospholipids of circulating lipoprotein particles or bacterial surfaces. This is termed the contact phase and results in the conversion of prekallikrein to kallikrein, which in turn catalyzes the activation of Factor XII to activated Factor XII. FXIIa promotes the activation of Factor XI to FXIa, causing the release of bradykinin from high molecular weight kininogen.
Factor IX is a proenzyme that contains vitamin K dependent �?carboxyglutamate residues, whose serine protease activity is activated following Ca2binding to the�?carboxyglutamate residues. In the presence of Ca2�? FXIa catalyzes the activation of Factor IX to FIXa. FIXa catalyzes the activation of Factor X to FXa, through interaction with the protein cofactor VIII. The extrinsic coagulation cascade is initiated following vascular injury by exposure of tissue factor to circulating plasma coagulation factors. TF and activated Factor VII catalyze the conversion of Factor X to FXa. The TF/FVIIa complex also catalyzes the activation of Factor IX of the intrinsic pathway, which in turn catalyzes the activation of Factor X. FXa, the point where the two coagulation cascades meet, catalyzes the activation of prothrombin to form thrombin. The activation of thrombin occurs on the surface of activated platelets and requires formation of a prothrombinase complex. This complex is composed of the platelet phospholipids, phosphatidylinositol and phosphatidylserine, Ca2�? Factors Va and Xa, and prothrombin. Thrombin catalyzes the conversion of fi brinogen t