New targets for antithrombotic drugs

The normal hemostatic process is initiated by disruption in the vascular continuity and exposure of the subendothelial components. Platelets adhere to subendothelium-bound von Willebrand factor via glycoprotein (GP) Ib complex. This initial interaction per se and the release of platelet agonists transduce signals that lead to the rise in intracellular Ca(2+). The rise in Ca(2+) induces shape change, prostaglandin synthesis, release of granular contents and conformational changes in platelet Gp IIb-IIIa. Gp IIb-IIIa in activated platelets becomes competent to bind fibrinogen and other adhesive proteins and mediates platelet cohesion (primary hemostatic plug). Furthermore, the activated platelet surface provides an efficient catalytic surface for the coagulation reactions, ultimately resulting in the formation of fibrin (secondary hemostasis). Normally the hemostatic process plays a delicate balance between keeping the blood in the fluid state to maintain flow and rapidly forming an occluding plug following vessel injury. Thrombosis occurs because of alteration in this delicate balance. Consequences of thrombosis are a major cause of morbidity and mortality in industrialized countries. Arterial thrombosis occurs in the setting of previous vessel wall injury mostly because of atherosclerosis, while venous thrombosis occurs in areas of stasis. The recent advances in our understanding of the hemostatic process have led to a better elucidation of the mechanism of action of many antithrombotic drugs and identification of new targets for drug development. The molecular target of the well known antiplatelet drug ticlopidine has been identified. Large numbers of IIb-IIIa inhibitors have been developed based on the crystal structure of a potent antagonist echistatin. The mechanism of action of heparin has been defined at the molecular level. As a result a synthetic pentasaccharide, based on antithrombin-binding domain of heparin, has been developed and tested successfully in clinical trials. New generation direct thrombin inhibitors are being developed based on the crystal structure of thrombin. Factor Xa has a critical position at the convergence of intrinsic and extrinsic pathway ways. The clinical tolerability and the efficacy of low molecular weight heparins led to the concept that inhibition of further thrombin generation, by blocking factor Xa alone, can be an effective way of preventing thrombus growth without inactivating thrombin. A large number of specific factor Xa inhibitors are under development. Some of these drugs have already undergone preliminary clinical trials and appear to be promising. Future clinical trials will determine whether these new drugs will provide better risk-benefit ratio in treatment of thrombotic disorders.