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αIIbβ3 Priming And Clustering By Orally Active And Intravenous Integrin Antagonists

R. Hantgan, M. C. Stahle, J. Connor, R. Connor, S. Mousa
Published 2007 · Chemistry

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Background: Drugs that block platelet–platelet and platelet–fibrin interactions via the αIIbβ3 (glycoprotein IIb/IIIa) receptor are used daily in patients undergoing percutaneous coronary interventions. Along with expected increases in spontaneous bleeding, clinical trials have revealed a surprising increase in thrombosis when these drugs are used without other anticoagulants. A better understanding of their mechanisms can minimize these risks. Objectives: This study tested the hypothesis that interventions designed to block fibrinogen binding inevitably leave the αIIbβ3 receptor in an activated state. It compared the effects on platelet function and αIIbβ3 conformation of the orally active compounds orbofiban and roxifiban, the i.v. agents eptifibatide and tirofiban, and echistatin, an arginine‐glycine‐aspartate (RGD) disintegrin. Methods: The integrin antagonist concentrations required to saturate platelets and to block platelet–platelet and platelet–fibrin interactions were determined by flow cytometery, aggregometry, and clot‐based adhesion assays, respectively. Analytical ultracentrifugation measured each antagonist's effects on the solution structure of αIIbβ3. Fluorescence anisotropy provided equilibrium and kinetic data for integrin:antagonist interactions. Results: Both orally active drugs bound more tightly and inhibited platelet aggregation and adhesion to fibrin more effectively than echistatin. Analytical ultracentrifugation yielded this order for perturbing αIIbβ3 conformation (priming) and promoting oligomerization (clustering): echistatin > eptifibatide > orbofiban > tirofiban > roxifiban. Roxifiban was also most effective at disrupting the rapidly forming/slowly dissociating αIIbβ3:echistatin complex. Conclusions: Our results suggest that the same molecular mechanisms that enable glycoprotein IIb/IIIa inhibitors to bind tightly to the αIIbβ3 receptor and block fibrinogen binding contribute to their ability to perturb the resting integrin's conformation, thus limiting the safety and efficacy of both oral and i.v. integrin antagonists.
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