Comment on Reininger et al, page 3537
In this issue of Blood, Reininger and colleagues describe a new mechanism of microparticle generation involving shear-dependent extraction of membrane fragments from the surface of platelets.
First described 40 years ago as the “coagulant material in minute particle form” in platelet-poor plasma (otherwise termed platelet dust), microparticles have been the subject of considerable debate and controversy over the years, particularly in the context of blood coagulation in healthy individuals.1,2 However, recent studies from a number of laboratories have convincingly demonstrated an important role for microparticles in thrombus development, heralding a renaissance in the field. But a number of vexing issues remain, including a lack of definitive information on the predominant cellular origin of circulating microparticles and the mechanism of microparticle tissue factor activation, as well as an incomplete understanding of the molecular basis for microparticle generation in vivo.FIG1
Using sophisticated imaging techniques, Reininger and colleagues demonstrate a unique mechanism of microparticle generation, in which microparticle-sized membrane fragments are physically “extracted” from the surface of platelets under the influence of high shear forces (see figure). It has recently been demonstrated that during adhesion to matrix proteins such as von Willebrand factor (VWF), platelets form small, localized adhesion contacts that transiently anchor the cell to the matrix surface.3,4 Under the influence of hydrodynamic flow, the cell body is dragged downstream from the point of matrix contact, pulling membrane from the cell surface. These elongated membrane tubes (termed tethers) are the only connection from the main cell body to localized adhesion points and, as such, play a key role in maintaining platelets in close proximity to thrombogenic surfaces (see figure). Membrane tethers have been extensively studied in a number of cell types but have only recently been identified in platelets.3,4 Reininger et al demonstrate that tethers can be as much as 30 μm long, with the platelets ultimately adopting a ball-on-a-string appearance. At such lengths, membrane tethers presumably exhaust platelet membrane reserves, with the membrane becoming unstable and prone to rupture by high shear forces. Thus, the authors raise the possibility that physical extraction of membrane tethers may represent a novel biomechanical mechanism of generating microparticles that is particularly relevant to pathologic shear conditions. Reininger and colleagues posit that these tethers have procoagulant properties due to phosphatidylserine and low-level tissue factor expression, suggesting a potentially novel mechanism of promoting thrombin generation under high shear.
The finding of localized biomechanical generation of microparticles on thrombogenic surfaces is interesting and potentially important and should stimulate further investigation into the relationship between shear and microparticle formation. Typically, the extrusion of procoagulant microparticles from the surface of platelets and other cell types involves proteolytic shedding mechanisms linked to cell stimulation by potent agonists or following apoptosis. It remains to be seen whether proteolytic shedding is the predominant mechanism of microparticle generation under lower shear conditions and whether biomechanically derived particles become progressively more important at higher shear. Nonetheless, these findings raise interesting issues and should stimulate further investigation into the precise relationship between the earliest events of platelet adhesion and the subsequent initiation of blood coagulation, a topic that remains as uncertain today as it did when microparticles were first discovered. ▪