Platelet procoagulant membrane dynamics: a key distinction between thrombosis and hemostasis?

Understanding the differences between physiological hemostasis and pathological thrombosis at molecular and cellular levels is a long-standing goal of platelet and coagulation biology. Such a distinction will pave the way for designing strategies to pharmacologically inhibit thrombosis without an increased concomitant tendency to bleed. Given that bleeding is the most common adverse effect associated with antithrombotics, with some cases being life-threatening, it is essential to distinguish between hemostasis and thrombosis. A principal difference is that hemostasis and thrombosis do not occur in the same local environment; while hemostasis occurs within tissue in the extravascular space, thrombosis is essentially an intra-vascular process (Figure 1). Additionally, although hemostasis and thrombosis share common pathways at a molecular level, increasing evidence has demonstrated that they are mechanistically distinct. For example, animal model gene knockout (KO) or inhibition of coagulation factor XI (FXI), 1,2 FXII, 3,4 glycoprotein VI (GPVI), 5-8 water channel aquaporin-1 (AQP1), 9 or protein kinase C alpha 10 show no signi fi cant bleeding defects but markedly affect arterial thrombosis. Additionally, pharmacologic inhibition of FXI 11,12 and FXII 13 in preclinical trials provides evidence that hemostasis and thrombosis can be uncoupled. In this commentary, we propose the hypothesis that platelet procoagulant membrane ballooning and microvesiculation, collectively termed procoagulant membrane dynamics (PMD), which amplify the procoagulant response in platelets, could provide a mechanistic distinction between hemostasis and thrombosis