Active site-blocked activated factor VII as an effective antithrombotic agent: mechanism of action

The tissue factor (TF) coagulation pathway is initiated when circulating fa ctor (F)VII(a) encounters TF, a cell surface glycoprotein, as a result of v ascular injury or pathological perturbation. TF-induced coagulation plays a primary role in hemostasis and also in the pathogenesis of various thrombo tic disorders. Recent studies suggest that activation of the TF-pathway may also contribute to other pathophysiological processes by altering intracel lular responses, either directly or via activated factor X (Dia) and thromb in generation. Therefore, suppression of the aberrant expression of TF/FVII a on cell surfaces not only prevents thrombotic disorders but may also prov ide other protective effects. Recent ex-vivo and in-vivo experiments docume nt the effectiveness of active site-blocked activated factor VII(FVIIai) in inhibiting TF-mediated injury. It is generally believed that FVIIai exerts its effects by limiting the formation of functional TF/FVIIa complexes by directly competing with plasma FVII(a) for Limited available TF sites on ce ll surfaces. Although such competition can explain the effectiveness of FVI Iai immediately after administration, it is not clear how it exerts its pro longed effects. In this manuscript, we summarize the use of FVIIai as an an tithrombotic agent in various model systems and discuss potential mechanism s by which FVIIai may exert protective effects. Blood Coagul Fibrinolysis 1 1 (suppl 1):S135-S143 (C) 2000 Lippincott Williams & Wilkins.