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In response to a variety of proaggregatory stimuli such as thrombin, adenosine diphosphate (ADP), or collagen, platelets synthesize eicosanoids, biologically active metabolites derived from arachidonic acid (Fig. 1).

Blood coagulation is initiated following injury to the blood vessel wall through the exposure of tissue factor, which mediates the activation of circulating factor VII. Activated factor VIIa forms a complex with tissue factor and triggers the subsequent steps in the activation of the coagulation system, ultimately culminating in the conversion of prothrombin to thrombin (–). The platelet membrane surface is crucial for this process, providing a milieu, referred to as the prothrombinase complex, for efficient assembly of the coagulation complexes and localization of the procoagulant response. Indeed, recent data have even implicated platelets in the initiation of coagulation as they acquire circulating forms of tissue factor, generated from other cells, on their surface (,). Thrombin mediates fibrin formation and plays a critical role in the inflammatory responses (); thus, the regulation of prothrombin activation by the platelet membrane has broad physiological and pathophysiological implications.

Platelet activation results in a complex series of changes including a physical redistribution of receptors, changes in the molecular conformation of receptors, secretion of granule contents, development of a procoagulant surface, generation of platelet-derived microparticles, and formation of leukocyte-platelet aggregates. Each of these changes can potentially be used as a marker of platelet activation. Whole blood flow cytometry () is the method of choice for the measurement of all these changes, except the secretion of soluble molecules, which are usually measured by enzyme-linked immunosorbent assay (ELISA). Whole blood flow cytometry has many advantages, including: only minuscule volumes (∼5 µL) of blood are required; platelets are directly analyzed in their physiological milieu of whole blood; the minimal manipulation of samples prevents artifactual in vitro activation and potential loss of platelet subpopulations; both the activation state of circulating platelets and the reactivity of circulating platelets can be determined; and a spectrum of different activation-dependent changes can be determined. The specific methodological details of the use of flow cytometry to measure platelet activation are described elsewhere (–).

The platelet is a circulating anucleate cell particle created from the cytoplasm of megakaryocytes in the bone marrow from whence it derives much of its cytoplasmic content. Deposited at sites of vascular injury, its role in the processes of thrombosis and haemostasis is well defined. Many important insights into the platelets haemostatic role were gained through genetic studies of rare inherited bleeding disorders such as Glanzmann’s thrombesthenia and Bernard-Soulier disease (,). It is now clear, however, that its physiological role extends beyond that of thrombosis to include regulation of inflammation, tissue repair, and the immune response, and one could argue that these are its predominant functions ().

Antiplatelet therapy has become indispensable in modern-day cardiology practice. Over 200,000 patients have been studied in randomized controlled trials of antiplatelet agents for cardiovascular diseases, supporting diverse clinical indications including primary and secondary preventions of thromboembolic diseases. The 2002 updated Antithrombotic Trialist Collaboration meta-analysis of antiplatelet trials established the clinical benefit of antiplatelet agents in patients at high risk of vascular events (such as those with underlying coronary artery disease, prior history of stroke, peripheral artery disease, and atrial fibrillation) () (Fig. 1). A detailed discussion encompassing all clinical indications of antiplatelet therapy is beyond the scope of this chapter. We will focus on representatives of the three major classes of antiplatelet agents (aspirin, thienopyridines, glycoprotein (GP)IIb-IIIa receptor antagonists) highlighting sentinel clinical trial results of coronary disease and interventions, and discuss platelet function assessments.

Since the 1970s, the role of antiplatelet therapy in patients with coronary artery disease has become established. Aspirin was the first drug to be used as an antiaggregant. Although early trials of aspirin lacked adequate statistical power to detect clinical benefits, two metaanalyses by the antiplatelet trialist group established the place of aspirin in the management of coronary artery disease and provided significant insight into the lack of a documented dose-response effect (,). Although the administration of aspirin to suitable patients still lags behind desired targets, most surveys indicate that more than 90% of appropriate patients are treated with it at the time of hospital discharge.