Recombinant factor VIIa restores aggregation of αIIbβ3-deficient platelets via tissue factor–independent fibrin generation

Abstract

AbstractRecombinant factor VIIa (rFVIIa) is a safe and effective prohemostatic drug for patients with Glanzmann thrombasthenia (GT). However, the mechanism of action of rFVIIa in these patients is still unclear. Although patients with GT are characterized by a complete absence of platelet aggregation to a variety of agonists, it has been shown that GT platelets are able to form aggregates, provided polymerizing fibrin is present. We studied the effect of rFVIIa-mediated fibrin formation on aggregation of αIIbβ3-deficient platelets. When washed platelets from GT patients or platelets from healthy volunteers treated with an arginyl-glycyl-aspartyl–containing peptide were activated with collagen in the presence of rFVIIa and purified coagulation factors X, II, and fibrinogen, complete aggregation occurred after a lag phase. Fibrin generation proceeded via rFVIIa-mediated thrombin generation on the activated platelet surface independently of tissue factor. Electron microscopic analysis of αIIbβ3-independent platelet aggregates showed a densely packed structure suggestive of a true platelet-fibrin interaction and not via trapping of platelets into a fibrin network. Also, rFVIIa-mediated αIIbβ3-independent aggregation was demonstrated under conditions of flow using a collagen-coated surface. In conclusion, the efficacy of rFVIIa in GT patients might be explained by induction of αIIbβ3-independent platelet aggregation, which compensates the lack of αIIbβ3-dependent aggregation.