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Hoffman M. Monroe DM 3rd. Roberts HR., Activated factor VII activates factors IX and X on the surface of activated platelets: thoughts on the mechanism of action of high-dose activated factor VII. Blood Coagulation & Fibrinolysis. 9 Suppl 1:S61-5, 1998.
High levels of recombinant activated factor VII (rFVIIa; NovoSeven, Novo Nordisk) have been found to be effective in providing hemostasis in hemophiliacs and in normal individuals with acquired inhibitors to factor VIII (FVIII) or FIX. However, the mechanism of this therapeutic effect of FVIIa is unclear. Opinion is divided over whether high-dose FVIIa therapy works primarily by a tissue factor (TF)-dependent or -independent mechanism. The authors originally favored a TF-dependent mechanism; however, we have recently found that, at levels comparable with those attained therapeutically, FVIIa activates enough FX on activated platelets to restore platelet surface thrombin generation. These data now lead us to favor a primarily (although not necessarily exclusively) TF-independent mechanism for the hemostatic effect of high-dose FVIIa. The authors believe that a platelet surface localization of FVIIa activity explains its safety and efficacy, as well as its hemostatic effect in patients with thrombocytopenia and platelet function defects. Localization on activated platelets would tend to restrict the activity of FVIIa to sites of injury. Activation of FX on the platelet surface in hemophiliacs would provide FXa in a favorable location to escape inhibition by plasma protease inhibitors and be incorporated into platelet prothrombinase complexes. Activation of FIX and FX on platelet surfaces in thrombocytopenia would result in more thrombin generation per platelet, possibly leading to formation of a stable fibrin network even in the absence of an optimal initial platelet plug.
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