Thrombin is a central bioregulator of coagulation and is therefore a key target in the therapeutic prevention and treatment of thromboembolic disorders, including deep vein thrombosis and pulmonary embolism. The current mainstays of anticoagulation treatment are heparins, which are indirect hrombin inhibitors, and coumarins, such as warfarin, which modutate the synthesis of vitamin K-dependent proteins. Although efficacious and widely used, heparins and coumarins have limitations because their pharmacokinetics and anticoagulant effects are unpredictable, with the risk of bleeding and other complications resulting in the need for close monitoring with their use. Low-molecular-weight heparins (LMWHs) provide a more predictable anticoagulant response, but their use is limited by the need for subcutaneous administration. In addition, discontinuation of heparin treatment can result in a thrombotic rebound due to the inability of these compounds to inhibit clot-bound thrombin. Direct thrombin inhibitors (DTI) are able to target both free and clot-bound thrombin. The first to be used was hirudin, but DTIs with lower molecular weights, such as DuP 714, PPACK, and efegatran, have subsequently been developed, and these agents are better able to inhibit clot-bound thrombin and the thrombotic processes that take place at sites of arterial damage. Such compounds inhibit thrombin by covalently binding to it, but this can result in toxicity and nonspecific binding. The development of reversible noncovalent DTIs, such as inogatran and melagairan, has resulted in safer, more specific and predictable anticoagulant treatment. Oral DTIs, such as ximelagatran, are set to provide a further breakthrough in the prophylaxis and treatment of thrombosis. Key Words:Anticoagulation-Thrombin-Heparin-Coumarin-Direct thrombin inhibitor (DTI)-Ximelagatran. ¡ Coagulation is the body's primary defense mechanism ! for the prevention of bleeding after tissue injury. Once triggered, coagulation consists of a series c~f ~~p~ise, ~c~r-dinted reactions involving specific plasma proteins and blood cells, culminating in the formation of an insoluble fibrin clot (1). A key factor within this system is thrombin (2), which constitutes the final common mediator both of the intrinsic and the extrinsic coagulation pathways, and mediates the proteolytic cleavage of fibrinogen to fibrin molecules, which subsequently become cross-linked (Fig. 1). In addition, thrombin promotes platelet activation and therefore plays a major role in the different stages of thrombus formation (3). Furthermore, thrombin not only stimulates coagulation by activating the cofactors of tenase and prothrombinase complexes (e.g., factors VIII and V), but also modulates coagulation and fibrinolysis by the t~romborn~dulin/prote'an C pathway, and by the alteration of endothelial functions. Thrombin also activates inflammatory processes
