Dissociation of glycoprotein IIb/IIIa antagonists from platelets does not result in fibrinogen binding or platelet aggregation

Background-The primary mechanism of action of glycoprotein (GP) IIb/IIIa an tagonists is inhibition of the final common pathway of platelet aggregation : fibrinogen binding to the GP IIb/IIIa complex. However, it has been repor ted that induction of fibrinogen binding and platelet aggregation is an int rinsic prothrombotic property of low-dose GP IIb/IIIa antagonists. These ap parently paradoxical results have been extensively referenced in the cardio logy literature. Methods and Results-By platelet aggregation and flow cytometry, we demonstr ate that (1) dissociation of GP IIb/IIIa antagonists (abciximab, tirofiban, eptifibatide, or xemilofiban) from platelets does not result in platelet a ggregation; (2) tirofiban and eptifibatide can induce a fibrinogen-binding- competent conformation or the GP IIb/IIIa receptor, but stable fibrinogen binding does not occur without fixation; (3) the slow off-rate of abciximab exposes only a small proportion of unblocked GP IIb/IIIa receptors at any time, and these also fail to stably bind fibrinogen; and (4) the GP IIb/III a antagonist-induced fibrinogen binding in some previously reported experim ents was probably the result of artifactual thrombin generation. Conclusions-Under physiological conditions, GP IIb/IIIa antagonists current ly in clinical use do not have an intrinsic activating property that result s in platelet aggregation or stable fibrinogen binding to GP IIb/IIIa.