Recombinant 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 alphaIIbbeta3-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 alphaIIbbeta3-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 alphaIIbbeta3-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 alphaIIbbeta3-independent platelet aggregation, which compensates the lack of alphaIIbbeta3-dependent aggregation.