Platelet Activation Gradients During Thrombus Formation

The hemostatic response requires the tightly regulated interaction of the coagulation system, platelets, other blood cells and components of the vessel wall at a site of vascular injury.  The dysregulation of this response may result in excessive bleeding if the response is impaired, and pathologic thrombosis with vessel occlusion and tissue ischemia if the response is overly robust.  Extensive studies over the past decades have sought to unravel the regulatory mechanisms that coordinate the multiple biochemical and cellular responses in time and space to ensure that an optimal response to vascular damage is achieved.  We and others have observed that platelet activation at a site of injury in vivo is heterogeneous, with a gradient of platelet activation extending from the site of injury.  Platelets immediately adjacent to the injured vessel wall are densely packed and fully activated forming a stably adherent core region.  This stable core is overlaid by a shell of less activated platelets that are more loosely packed.  Genetic and pharmacologic studies have shown that the formation of these regions is dependent on partially overlapping gradients of distinct platelet agonists, with ADP serving as a mediator of platelet recruitment and retention in the shell region, and thrombin necessary for full platelet activation in the core region.  The distribution of platelet agonists and other plasma solutes in time and space is in turn determined in part by their transport in the plasma microenvironments that evolve as platelets accumulate.  Platelet mass consolidation and the subsequent narrowing of the gaps between platelets are important mechanisms by which plasma solutes are retained within the platelet mass to promote platelet activation.  Consolidation also regulates the escape of plasma and platelet-derived bioactive molecules into the extravascular space.  These studies and others examining how cellular, biochemical and physical factors are integrated to shape the optimal response to vascular injury in vivo will be discussed.