Investigators have recently identified an important role for therapy using a monoclonal antibody directed against the platelet membrane glycoprotein IIb/IIIa receptor [5]. In an attempt to mimic the defect seen in patients with Glanzmann thrombasthenia, Coller and colleagues [6] induced and purified a monoclonal antibody that produced a thrombasthenic-like state in normal persons by blocking this receptor. Aspirin inhibits platelet aggregation by reducing the amount of thromboxane A₂, a potent trigger of platelet aggregation. However, even in the absence of thromboxane A₂, platelets may be induced to aggregate by other triggers, such as thrombin, subendothelial collagen, or stainless steel from intracoronary stents. Once platelets are activated, the platelet membrane glycoprotein IIb/IIIa receptors appear on the platelet surface; "adhesive macromolecule" fibrinogen or von Willebrand factor bind to these receptors and cross-link one activated platelet to another. By attaching to the receptors, the antibody prevents activated platelets from cross-linking. Therefore, regardless of the trigger responsible for activating platelets, this new drug inhibits the final common path of platelet aggregation.

Large randomized, controlled studies have established a benefit for the use of these glycoprotein IIb/IIIa receptors in coronary artery disease. The EPIC trial investigators [5] reported that bolus administration of the receptor antibody during coronary angioplasty, followed by a 12-hour infusion, reduced the incidence of acute ischemic events by 35% compared with placebo. Simoons and colleagues [7] reported a reduced incidence of subsequent myocardial infarction and improved coronary flow in patients with unstable angina. More recently, a cyclic peptide receptor antagonist, integrelin, has been tested in patients having angioplasty and patients with unstable angina [8]. In addition, a small nonpeptide receptor inhibitor has been tested in patients with coronary disease [9]. Lastly, a 6-month angiographic follow-up of the original EPIC (Evaluation of C7E3 Fab in the Prevention of Ischemic Complications) cohort suggests that patients treated with the glycoprotein IIb/IIIa antibody had a reduced incidence of clinical restenosis compared with the patients receiving placebo [10]. Modification of concomitant heparin use has minimized the risk for bleeding with receptor antagonists.

The glycoprotein IIb/IIIa receptor is an integrin. Integrins belong to a large family of transmembrane proteins; this family is composed of associated and ß subunits that promote cellular adhesion and mediate cell-to-cell binding and cell-to-extracellular matrix binding. The integrin _IIb ß₃ (the glycoprotein IIb/IIIa receptor) mediates platelet binding. Its cousin, integrin (_V) ß₃ (the vitronectin receptor), appears to mediate cell-to-matrix binding, which is probably essential for angiogenesis [11], and cell migration and proliferation [12]. The "anti-integrin," that is, the monoclonal antibody to IIb/IIIa (ReoPro, Centocor B.V., Leiden, the Netherlands), is relatively nonspecific and also appears to block the vitronectin receptor. This overlap in activity of the monoclonal antibody to include the vitronectin receptor may explain the 26% reduction in clinical restenosis seen in the antibody recipients followed for 6 months in the EPIC study. Because the vitronectin receptor plays a major role in angiogenesis, nonspecific inhibition of this receptor as well as of the initial target—the IIb/IIIa receptor—may have far-reaching consequences. In contrast, several of the other IIb/IIIa receptor antagonists are more specific for IIb/IIIa and have little or no effect on other integrins. Whether these differences in specificity will affect clinical efficacy is not yet known.

The development of the anti-integrin c7E3 against the IIb/IIIa receptor constitutes a major advance in the field of antithrombotic therapy for coronary artery disease. With the evolution of more uniformally bioavailable oral agents [13], the time-honored role of aspirin may become eclipsed. The larger implications about anti-integrin therapy for preventing angiogenesis in neoplasia are provocative but remain to be clarified.