CHAPTER 8 – Integrin αIIbβ3

Platelets contribute to the normal circulation of blood through the preservation of vascular integrity and prevention of hemorrhage after injury. Although the role of platelets in thrombus formation is a necessary defense mechanism, excessive thrombus formation on unstable atherosclerotic plaques can obstruct blood flow and lead to acute myocardial infarction or stroke. 1-3 Therefore, platelet-induced thrombus formation is both a pivotal physiological and pathological response. The capacity of platelets to form a thrombus depends on their ability to aggregate. At a molecular level, platelet aggregation is mediated by a specific receptor on the platelet surface, αIIbβ3 (also known as glycoprotein [GP]IIb-IIIa), a member of the integrin family. 4,5 Central to the function of integrin αIIbβ3 is its capacity to undergo activation, a transition from a low-affinity state (resting state) to a high-affinity state (active state) for its extracellular ligands. This transformation of αIIbβ3 allows it to bind divalent fi brinogen or multivalent von Willebrand factor (VWF),6,7 which can act as bridging molecules between platelets to form aggregates. Recognition of other ligands, notably vitronectin, fibronectin, and thrombospondin,8-10 by αIIbβ3 may help to mediate platelet adhesion to the subendothelial matrix and to regulate platelet aggregation. The key role of αIIbβ3 in mediating platelet aggregation, and the demonstration many years ago that blockade of this function inhibits this response,11,12 defi ned this receptor as a potential target for antithrombotic therapy. Indeed, this therapeutic strategy has come to realization. Inhibition of platelet aggregation using intravenously administered antibody, peptide, and nonpeptide derivatives as αIIbβ3 (GPIIb-IIIa) antagonists has been accepted clinically and is used broadly to treat and prevent thrombosis in the settings of percutaneous coronary intervention and acute coronary syndromes13 (see Chapter 62). Considerable information on αIIbβ3 has evolved from numerous basic and clinical investigations, but a full understanding of its functions is far from resolved. αIIbβ3 is the focus of this chapter, with a primary emphasis on its structure and activation. The molecular events that regulate activation of αIIbβ3 have been termed collectively inside-out signaling . The outside-in signaling that results from ligand binding to αIIbβ3 is considered separately in Chapter 17.