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(Circulation. 2001;104:1374.)
© 2001 American Heart Association, Inc.

Clinical Investigation and Reports

Dissociation of Glycoprotein IIb/IIIa Antagonists From Platelets Does Not Result in Fibrinogen Binding or Platelet Aggregation

Andrew L. Frelinger, III, PhD; Mark I. Furman, MD; Lori A. Krueger, BA, ART; Marc R. Barnard, MS; Alan D. Michelson, MD

From the Center for Platelet Function Studies (A.L.F., M.I.F., L.A.K., M.R.B., A.D.M.) and the Division of Cardiovascular Medicine (M.I.F.), University of Massachusetts Medical School, Worcester, Mass.

Correspondence to A.L. Frelinger III, PhD, Center for Platelet Function Studies, University of Massachusetts Medical School, 55 Lake Ave North, Worcester, MA 01655. E-mail Frelinger{at}platelets.org

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.

Key Words: platelets • inhibitors • glycoproteins • fibrinogen • receptors

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