Recombinant factor VIIa (rFVIIa) has been developed for treatment of inhibitor-complicated hemophilia. Increasing clinical evidence shows that rFVIIa also appears safe and effective as pro-hemostatic agent in various other clinical disorders including patients with thrombocytopenia. Relatively little is known about the mechanism of action of rFVIIa in hemophilia and its various other potential indications. It is generally accepted that rFVIIa functions by enhancement of thrombin generation at the site of injury. It is, however, unknown if and how this affects platelet adhesion and aggregation. Previously, we have shown that rFVIIa-mediated thrombin generation substantially enhances deposition of platelets from patients with Glanzmann thrombasthenia (a qualitative or quantitative deficiency of the integrin αIIbβ3) to subendothelial proteins (
). Here, we investigated the effect of rFVIIa-mediated thrombin generation on platelet adhesion and aggregation under flow conditions at normal and reduced platelet count. A mixture of washed platelet and red cells was perfused over collagen or fibrinogen in presence or absence of a thrombin-generating system consisting of purified coagulation factors rFVIIa, X, and prothrombin in the presence of calcium chloride. Addition of this thrombin-generating system enhanced platelet adhesion and aggregation to collagen and adhesion and spreading to fibrinogen at normal platelet count and at platelet numbers as low as 10.000/μl. rFVIIa-mediated thrombin generation enhanced the activation state of platelets adhered under flow as measured by intracellular calcium fluxes, and enhanced the exposure of procoagulant phospholipids as measured by annexin A5 binding. It was shown that FITC-labeled rFVIIa bound to collagen-adhered platelets under flow conditions in experiments in which whole blood from severely thrombocytopenic patients was used. We believe thrombin is generated by platelet-bound rFVIIa independent of tissue factor. Taken together, increased platelet adhesion and aggregation by rFVIIa-mediated thrombin formation may explain the therapeutic effects of rFVIIa in thrombocytopenic conditions and in patients with a normal platelet count by (1) enhancement of primary hemostasis and (2) enhancement of procoagulant surface leading to elevated fibrin formation. These platelet-promoting effects of rFVIIa might also, in part, explain the therapeutic effects of rFVIIa in other indications.
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