Integrin α IIb β 3 and Its Antagonism

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.