Affiliation:
1. From the Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Departments of Cardiovascular Medicine (M.J.Q., E.J.T.) and Molecular Cardiology (T.V.B., J.Q., E.F.P.), Cleveland Clinic Foundation, Cleveland, Ohio.
Abstract
α
IIb
β
3
, the major membrane protein on the surface of platelets, is a member of the integrin family of heterodimeric adhesion receptors. The α
IIb
and β
3
subunits are each composed of a short cytoplasmic tail, a single transmembrane domain, and a large, extracellular region that consists of a series of linked domains. Recent structural analyses have provided insights into the organization of this and other integrins and how a signal is initiated at its cytoplasmic tail to transform the extracellular domain of α
IIb
β
3
into a functional receptor for fibrinogen or von Willebrand factor to support platelet aggregation and thrombus formation. These functions of α
IIb
β
3
have been targeted for antithrombotic therapy, and intravenous α
IIb
β
3
antagonists have been remarkably effective in the setting of percutaneous coronary interventions, showing both short-term and long-term mortality benefits. However, the development of oral antagonists has been abandoned on the basis of excess of mortality in clinical trials, and the extension of therapy with existing α
IIb
β
3
antagonists to broadly treat acute coronary syndromes has not fully met expectations. An in-depth understanding of how antagonists engage and influence the function of α
IIb
β
3
and platelets in the context of the new structural insights may explain its salutary and potential deleterious effects.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine