A novel approach to treat bleeding episodes in patients with Glanzmann thrombasthenia (GT) and perhaps also in patients receiving ␣ IIb ␤ 3 inhibitors is the administration of recombinant factor VIIa (rFVIIa). The mechanism of action of rFVIIa in these patients is, however, still unclear. We studied the effect of rFVIIamediated thrombin formation on adhesion of ␣ IIb ␤ 3 -deficient platelets under flow conditions. Adhesion of ␣ IIb ␤ 3 -deficient platelets to the extracellular matrix (ECM) of stimulated human umbilical vein endothelial cells or to collagen type III was studied using a model system with washed platelets and red cells. When ␣ IIb ␤ 3 -deficient platelets were perfused over the surface at arterial shear rate for 5 minutes, a low surface coverage was observed (GT platelets, mean ؎ SEM, 37.5% ؎ 5.0%; normal platelets preincubated with an RGD-containing peptide, 7.4% ؎ 2.1%). When rFVIIa, together with factors X and II, was added to the perfusate, platelet deposition significantly increased (GT platelets, mean ؎ SEM, 67.0% ؎ 4.3%; normal platelets preincubated with an RGD-containing peptide, 48.2% ؎ 2.9%). The same effect was observed when normal platelets were pretreated with the commercially available anti-␣ IIb ␤ 3 drugs abciximab, eptifibatide, or tirofiban. It was shown that tissue factor-independent thrombin generation (presumably induced by binding of rFVIIa to adhered platelets) was responsible for the increase in platelet deposition. In conclusion, defective adhesion of ␣ IIb ␤ 3 -deficient platelets to ECM can be restored by tissue factor-independent rFVIIa-mediated thrombin formation. The enhanced generation of platelet procoagulant surface facilitates fibrin formation, so that lack of platelet aggregate formation might be compensated