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

Circulation. 2001 Sep 18;104(12):1374-9. doi: 10.1161/hc3701.095950.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding, Competitive / drug effects
  • Binding, Competitive / physiology
  • Blood Platelets / cytology
  • Blood Platelets / drug effects*
  • Blood Platelets / metabolism
  • Dose-Response Relationship, Drug
  • Fibrinogen / metabolism*
  • Flow Cytometry
  • Hirudins / pharmacology
  • Humans
  • Platelet Aggregation / drug effects*
  • Platelet Aggregation / physiology
  • Platelet Aggregation Inhibitors / metabolism
  • Platelet Aggregation Inhibitors / pharmacology*
  • Platelet Glycoprotein GPIIb-IIIa Complex / antagonists & inhibitors*
  • Platelet Glycoprotein GPIIb-IIIa Complex / chemistry
  • Protein Binding / drug effects
  • Protein Conformation / drug effects
  • Tissue Fixation

Substances

  • Hirudins
  • Platelet Aggregation Inhibitors
  • Platelet Glycoprotein GPIIb-IIIa Complex
  • Fibrinogen