Although every student of hematology learns that platelets first adhere to the injured vessel wall, change shape, get activated, then aggregate to form the platelet plug, it is just not quite that simple.
In the current issue, Maxwell and colleagues show that thrombus formation in vivo involves a 2-step process for platelet aggregation, and this process is distinct from the events that characterize thrombus formation either under low shear (0-1000 s−1) or at very high shear (> 10 000 s−1). But what happens at physiologic shear, between 1000 and 10 000 s−1? In these studies in the microcirculation of a live rat, thrombus formation is initiated by photoactivation of rose bengal dye to injure the vessel wall through an oxidative process. This is one of a number of nonphysiologic thrombosis models that are widely used in animal models of thrombosis.
Unstimulated platelets circulate in the blood as discoid structures. In the current work, these discoid platelets in the circulation come in contact with discoid platelets immobilized on the vessel wall, and the differential interference contrast (DIC) microscopy images of this process are striking. Circulating platelets become associated with thrombus-bound platelets, with the moving platelet sliding along the immobilized platelet to maximize cell-cell contact.
The first phase of platelet aggregation that occurs at physiologic shear rates in the arterial circulation involves shear-induced formation of membrane tethers between platelets. The higher the shear rate, the more tethers that are observed, and the larger the (reversible) platelet aggregates. The platelets, in their discoid shape, become linked side to side through these tethers. At these shear rates, these tethers require the interaction of both platelet GPIb with matrix von Willebrand factor and the integrin αIIbβ3 with matrix fibrinogen. In addition, the platelets must be activated and engage the adhesive function of both of the platelet receptors GPIb and αIIbβ3.
During the second phase, platelets undergo their characteristic shape change and demonstrate irreversible platelet adhesion. The release of ADP is critical to the recruitment of additional platelets into the developing thrombus. The dynamics of platelet aggregation and thus thrombus growth are greatly influenced by 3 factors: (1) high shear stress, which leads to increased number of tethers and tighter binding; (2) the number of platelets and thus the platelet surface density; and (3) matrix reactivity, with the availability of certain adhesive proteins, GPIb and αIIbβ3, that are counterreceptors of other adhesion molecules.
Thrombosis remains the leading cause of death in Western society. Given the importance of this pathologic process, understanding its molecular and cellular details in a living animal has implications for the identification of appropriate targets and for therapeutic design.
Conflict-of-interest disclosure: The author declares no competing financial interests. ▪
