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

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Center for Platelet Function Studies; Department of Pediatrics

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Binding, Competitive; Blood Platelets; Dose-Response Relationship, Drug; Fibrinogen; Flow Cytometry; Hirudins; Humans; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; inhibitors; Protein Binding; Protein Conformation; Tissue Fixation


Life Sciences | Medicine and Health Sciences


BACKGROUND: The primary mechanism of action of glycoprotein (GP) IIb/IIIa antagonists is inhibition of the final common pathway of platelet aggregation: fibrinogen binding to the GP IIb/IIIa complex. However, it has been reported that induction of fibrinogen binding and platelet aggregation is an intrinsic prothrombotic property of low-dose GP IIb/IIIa antagonists. These apparently paradoxical results have been extensively referenced in the cardiology literature. METHODS AND RESULTS: By platelet aggregation and flow cytometry, we demonstrate that (1) dissociation of GP IIb/IIIa antagonists (abciximab, tirofiban, eptifibatide, or xemilofiban) from platelets does not result in platelet aggregation; (2) tirofiban and eptifibatide can induce a fibrinogen-binding-competent conformation of 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/IIIa antagonist-induced fibrinogen binding in some previously reported experiments was probably the result of artifactual thrombin generation. CONCLUSIONS: Under physiological conditions, GP IIb/IIIa antagonists currently in clinical use do not have an intrinsic activating property that results in platelet aggregation or stable fibrinogen binding to GP IIb/IIIa.

DOI of Published Version



Circulation. 2001 Sep 18;104(12):1374-9.

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