Editorial [Hot Topic: Anti-Platelet Therapy (Guest Editor: Susan S. Smyth)]

Blood platelets, small fragments derived from bone-marrow residing megakaryocytes, play a critical role in normal hemostasis and contribute to pathologic arterial thrombosis. They circulate in a resting state, capable of adhering to exposed subendothelial matrix in damaged vessels. Upon contact with damaged blood vessels or some foreign materials or as a result of the actions of soluble mediators, a series of intracellular signaling events are triggered to “activate” platelet functions. As a consequence of activation, platelets secrete granule contents, metabolize lipids such as arachidonic acid to create bioactive mediators, release microparticles into circulation, acquire the ability to aggregate with one another, interact with leukocytes, and serve as a surface for production of thrombin. The net effect is creation of a primary platelet plug that is reinforced by fibrin polymers generated by thrombin. Proper platelet function is essential during hemostasis to prevent blood loss. Defects in platelet number or function result in variably severe bleeding, especially mucocutaneous and, occasionally, intracerebral hemorrhage. The properties that are required to promote hemostasis can result in inadvertent platelet activation at sites of atherosclerotic plaque rupture/erosion or upon encounter with foreign objects, including vascular biomaterials and blood-borne pathogens. Pathologic platelet activation and aggregation thus contribute to the spontaneous and iatrogenic complications of atherosclerotic vascular disease, including myocardial infarction, stroke, and stent thrombosis. In order to accommodate their specialized functions, platelets have unique features that have proven to be excellent drug targets. Indeed, with the high prevalence of coronary heart disease (∼7% in the US adults over age 201), anti-platelet therapy has become one of the most commonly used classes of pharmaceuticals. In this theme issue, leading experts discuss aspects of platelet function and anti-platelet therapy, beginning with a historic perspective by Steinhubl. He describes the discerning early microscopic observations of Donne, Zimmerman, Schultze, Osler and others that set the stage for Bizzozero's work establishing platelets as a distinct element of blood, rather than a byproduct of or precursor to white or red blood cells. The article discusses the development of the initial platelet function tests and the first and still most widely used anti-platelet therapy, aspirin. The article traces the 100-year history of aspirin up to the landmark ISIS-2 study, published over 20 years ago, that established aspirin's anti-thrombotic effect and set the foundation for use of anti-platelet drugs in the treatment of acute coronary syndromes. Bailey and Campbell discuss current strategies to inhibit platelet function in both acute coronary syndromes and percutaneous coronary interventions, which generally involve dual antiplatelet therapy with the combination of aspirin and an antagonist of the platelet P2Y12 ADP receptor. They also describe ongoing clinical trials aimed at assessing the utility of antagonists of the platelet PAR1 thrombin receptor in the treatment of acute coronary syndrome and in patients with a previous history of myocardial infarction, stroke, or peripheral arterial disease. The other widely-used class of anti-platelet agents, the glycoprotein IIb/IIa inhibitors or GPI, is the subject of the article by Schneider. Rather than inhibiting platelet activation, GPIs block the final common step in platelet aggregation - binding of multivalent proteins such as fibrinogen to the GPIIb/IIIa complex on the platelet surface. The GPI class emerged as a consequence of extensive basic research of platelet biology and played an important role in establishing clinical utility of antiplatelet therapy. For reasons that are still not entirely clear, oral GPIs were associated with an increased risk of death, and their development was therefore abandoned. With the emergence of newer and more potent oral P2Y12 antagonists, the parental use of GPIs has largely been relegated to adjunctive therapy in the setting of percutaneous coronary intervention in individuals with higher thrombotic burden or risk. Bigalke, Gawaz and colleagues describe another potential anti-platelet target ? the major collagen receptor GP VI, a platelet specific protein that may also be useful as a diagnostic marker or as a tool for imaging platelet accumulation at sites of injury. Although other platelet proteins bind collagen, GP VI is essential for collagen-mediated platelet activation and is required for thrombosis in animal models that involve exposure of collagen in the vessel wall. In their article, Holly and Parise review systems biology approaches that are being applied to platelets to uncover novel and potentially safer anti-platelet strategies. The last three articles tackle clinical issues commonly encountered with the use of anti-platelet therapy. Because of their essential role in hemostasis, disruption of platelet function results in an increased risk of bleeding. Halim and Rao document the prevalence and risk of bleeding in the treatment of acute coronary syndromes. Whether newer anti-platelet therapies can be developed that minimize the risk of bleeding but retain efficacy remains to be determined. One current, but as of yet unproven, strategy to improve the benefit and reduce unnecessary risk associated with anti-platelet drugs is to monitor platelet function through ex vivo testing. Platelet function testing has clearly established substantial inter-individual variability in the degree of inhibition of platelet function observed in patients taking aspirin or the older P2Y12 antagonists, such as clopidogrel and ticlopidine. Sibling, Byrne and Kastrati review the role of platelet function testing and the characteristics of the available devices for monitoring platelet responses to therapy. Finally, Oestreich examines the links between genetic variants, platelet response to therapy, and clinical outcomes. Substantial advances in the use of anti-platelet therapy have occurred in the 100 years since the commercial availability of aspirin. Basic and clinical research have converged to illuminate the molecular underpinnings of the role of platelets in health and disease. While much remains to be learned about the optimal prevention and management of thrombosis, refinements in the use of anti-platelet drugs have undoubtedly played an important role in reducing morbidity and mortality associated with the complications of atherosclerotic vascular disease and are likely to be partially responsible for the ∼ 26% decline in the annual death rate due to coronary heart disease that occurred in the U.S. between 1997 and 20071. Future improvements in efficacy and safety of anti-platelet therapy will almost certainly involve tailored application to particular patient populations based on genetic or functional tests or other markers that predict risk and response to therapy.