The growing complexity of platelet aggregation

Abstract

Platelet aggregation, the process by which platelets adhere to each other at sites of vascular injury, has long been recognized as critical for hemostatic plug formation and thrombosis. Until relatively recently, platelet aggregation was considered a straightforward process involving the noncovalent bridging of integrin ␣ IIb ␤ 3 receptors on the platelet surface by the dimeric adhesive protein fibrinogen. However, with recent technical advances enabling real-time analysis of platelet aggregation in vivo, it has become apparent that this process is much more complex and dynamic than previously anticipated. Over the last decade, it has become clear that platelet aggregation represents a multistep adhesion process involving distinct receptors and adhesive ligands, with the contribution of individual receptorligand interactions to the aggregation process dependent on the prevailing blood flow conditions. It now appears that at least 3 distinct mechanisms can initiate platelet aggregation, with each of these mechanisms operating over a specific shear range in vivo. The identification of shear-dependent mechanisms of platelet aggregation has raised the possibility that vascular-bed-specific inhibitors of platelet aggregation may be developed in the future that are safer and more effective than existing antiplatelet agents. IntroductionThe propensity of platelets to clump together at sites of vascular injury was first recognized more than 100 years ago. [1][2][3][4] This phenomenon, most accurately described as platelet cohesion although more commonly referred to as platelet aggregation, was quickly identified as important for hemostatic plug formation. 5 It was also recognized at the time that platelets played a key role in the development of thrombosis, 6 but, it was not until almost a century later that it became widely accepted that platelets played a pivotal role in development of cardiovascular disease. 7 As a consequence, inhibitors of platelet aggregation have become increasingly important parts of the armamentarium for the prevention and treatment of many atherothrombotic disorders. 8,9 For more than 3 decades, the factors mediating platelet aggregation appeared conceptually straightforward, requiring a platelet stimulus (agonist), a soluble adhesive protein (fibrinogen), and a membrane-bound platelet receptor (integrin ␣ IIb ␤ 3 or GPIIb-IIIa), leading to a simple unified model of platelet aggregation ( Figure 1). Although these core elements remain fundamental, recent technical advances allowing real-time analysis of platelet aggregation in vivo have demonstrated a much more complex and dynamic process than previously anticipated. It is now widely accepted that one of the key elements influencing the platelet aggregation process is blood flow, with evidence that distinct aggregation mechanisms operate under different shear conditions. [10][11][12][13] This has raised the interesting possibility that vascular bed-specific inhibitors of platelet aggregation may be developed in the future and has stimulated a...

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