Potential New Targets for Antithrombotic Therapy

Thrombosis is the collective term for diseases caused by the localized accumulation of circulating blood elements within the vasculature that result in vessel occlusion. Conventional antithrombotic drugs target the coagulation pathways (e.g., heparins, warfarin, ximelagatran), platelet-dependent mechanisms (e.g., clopidogrel), or thrombi in situ (e.g., streptokinase). While marketed anticoagulants are very efficacious, they can paralyze hemostasis, which is a potentially fatal condition when left untreated. Accordingly, anticoagulants are only rarely used at fully or markedly efficacious doses, e.g., high dose heparin, for short periods of time in closely watched clinical situations. Ideally, new targets for therapy would lead to the development of agents that are specific for thrombusforming mechanisms without compromising hemostasis. However, our understanding of the molecular, cellular, and physical interactions that differentiate thrombosis vs. hemostasis is limited. Even in the absence of thrombosis-specific, targeting, new drugs should preferentially inhibit the thrombotic process at doses that are relatively safe. The symptomatology of hemostatic pathway alterations can serve as basis for rational target selection. Hemostatic disorders that are compatible with human life and potentially protective against thrombosis provide useful guidance for new pharmacologic strategies. Additionally, theoretical considerations and experimental data suggest that new strategies for antithrombotic therapy might include: 1) inhibition of intrinsic coagulation pathway activity, 2) reduction of circulating platelet count, 3) inhibition of platelet protease activated receptor-4, or 4) enhancement of endogenous protein C or thrombolytic pathways might safely improve antithrombotic therapy.