Platelets were first described as disklike structures by Osler in 1873 [1]. Seven years later, their anatomical structure and role in hemostasis and experimental thrombosis were described by Bizzozero [2]. An in vitro method to quantify platelet aggregation was reported by Born in 1962. Born stated that “If it can be shown that adenosine diphosphate (ADP) takes part in the aggregation of platelets in blood vessels, it is conceivable that adenosine monophosphate (AMP) or some other substance could be used to inhibit or reverse platelet aggregation in thrombosis” [3]. The observations of Born provided the fundamental basis for ex vivo measurement of platelet aggregation in patients with coronary artery disease (CAD) and for the development of antiplatelet agents. Antiplatelet agents that block these targets were either identified (aspirin) or developed (P2Y₁₂ and GPIIb/IIIa receptor blockers) during the past four decades. Currently, the latter agents constitute a major part of the pharmacological strategy to prevent thrombosis, an important cause of myocardial infarction and death [4].

Under normal circumstances, platelets circulate in an inactive form and don’t significantly interact with the vessel wall. In the setting of endothelial disease or a breach in the endothelial lining, platelets will attach to the vessel wall. Healthy vascular endothelium prevents platelet adhesion and subsequent activation by producing factors such as ectoADPase (CD39), prostaglandin I₂, and nitric oxide. Injury to the endothelium results in exposure of the subendothelial matrix resulting in adhesion, activation, and aggregation of platelets. The latter processes play important roles in coagulation and clot generation at the site of vascular injury ultimately preventing blood loss (hemostasis) and promoting healing [5].

Role of platelets during initiation of atherosclerosis and plaque formation

The normal endothelium loses its antithrombotic properties in the setting of hyperlipidemia, hypertension, smoking, obesity, insulin resistance, and inflammation. Dysfunctional endothelium is characterized by decreased expression of antithrombotic factors. There is enhanced expression of von Willebrand factor (vWF), selectins, tissue factor, fibronectin, integrin α_vβ₃, and plasminogen activator inhibitor and other proinflammatory cytokines, chemokines, and adhesion molecules. An activated but intact endothelium facilitates the adhesion and activation of circulating platelets. Activated platelets on the surface of the endothelium express proinflammatory cytokines and adhesion molecules that further facilitate the binding and internalization of leukocytes into the subendothelial space where they transform into macrophages. Moreover, changes in endothelial permeability and the composition of the subendothelial matrix facilitate the entry and retention of cholesterol-rich low-density lipoprotein (LDL) particles. The macrophages avidly engulf LDL cholesterol and transform into foam cells, leading to fatty streak and plaque formation. Activated platelets further enhance inflammation by expressing platelet factor 4, CD40 ligand, and interleukin-1β [5, 6].