platelet aggregation or activation responses, but instead lack of fibrin deposition at the site of vascular injury because of the disruption in PS exposure and subsequent lack of surface area for thrombin generation. 12 The molecular mechanism underlying this platelet defect has been determined to be defective expression of the anoctamin-6 gene (Ano-6), which is an essential component of calcium-activated chloride channels that couple with Na+ nonselective cation channels to promote fluid influx. PS exposure is dependent on calcium-dependent scramblase activity through the formation of Ca2+-activated Cl–channels.

In this article by Agbani and colleagues, the procoagulant activities of the platelet are characterized. They demonstrate that procoagulant platelets undergo distinctive cytoskeletal changes that define the balloon shape, enhance PS exposure, and ultimately lead to coagulation. With the use of 4-dimensional live-cell microscopy imaging to define and visualize this dynamic process, they elucidate a process that was previously ill-defined. In addition, this article defines platelet ballooning as a distinct process apart from platelet blebbing; the balloon shape is the result of disruption of the platelet microtubule cytoskeleton and an influx of fluid, and is dependent on Na+, Cl–, and water entry. They also demonstrate that the ballooning is linked to enhanced microparticle generation. To demonstrate the specificity of fluid entry in the process of platelet ballooning, they show that inhibition of Na+, Cl–, or water influx impairs ballooning, leading to disrupted procoagulant spreading and microparticle generation, and ultimately leading to impaired thrombin generation. The authors demonstrate that there is an increase in internal hydrostatic pressure that results from a coordinated Na+, Cl–, and water entry, which leads to balloon inflation. This is distinct from other areas that are undergoing blebbing, which is not dependent on fluid entry. In addition, the authors show that the ballooned area is the essential area for microparticle release, another key component to maintaining hemostasis. They have identified and termed this particular population of platelets ballooned and procoagulant-spread platelets. Ballooned and procoagulant-spread platelets break up to form procoagulant microvesicles and therefore increase the surface area of the PS-exposed membrane that supports procoagulant activity. The authors delineate the mechanism for water influx by identifying the selective channel through which the water entry is regulated. By using the defects identified in Scott syndrome, they linked this fluid entry to a mechanism of calcium entry resulting from defects in Ano-6. In Scott syndrome, platelets lack Ano-6; the authors believe that this disrupts coagulation through functional changes in the platelet procoagulant response by decreased balloon formation, lack of PS exposure, and ultimately diminished microparticle release. Based on the authors’ findings, this lack of Ano-6 leads to the inhibition of fluid entry because of the disruption of Ca2+ entry and Na+, Cl–shifts, leading to diminished platelet ballooning. The notion of platelet ballooning, however, is not without controversy. One unique feature of these procoagulant platelets is that the processes of blebbing, PS exposure, and microparticle generation resemble the process of cellular death. Others have hypothesized that platelets undergo the act of programmed cellular death to support the final stages of