Reduced platelet glycoprotein Ibα shedding accelerates thrombopoiesis and COX-1 recovery: implications for aspirin dosing regimen

Cardiovascular prevention with low-dose aspirin can be less effective in patients with a faster recovery of platelet cyclooxygenase (COX)-1 activity during the 24 hours dosing interval. We previously showed that incomplete suppression of TXA2 over 24 hours can be rescued by a twice daily aspirin regimen. Here we show that reduced platelet glycoprotein (GP)Ibα shedding characterizes patients with accelerated COX-1 recovery and may contribute to higher thrombopoietin production and higher rates of newly-formed platelets, escaping aspirin inhibition over 24 hours. Two-hundred aspirin-treated patients with high cardiovascular risk (100 with type 2 diabetes mellitus) were stratified according to the kinetics of platelet COX-1 activity recovery during the 10-24h dosing interval. Whole proteome analysis showed that platelets from patients with accelerated COX-1 recovery were enriched in proteins involved in cell survival, inhibition of apoptosis and cellular protrusion formation. In agreement, we documented increased plasma thrombopoietin, megakaryocyte maturation and proplatelet formation, and conversely increased platelet galactose and reduced caspase 3, phosphatidylserine exposure and ADAM17 activation, translating into diminished GPIbα cleavage and glycocalicin release. Treatment of HepG2 cells with recombinant glycocalicin led to a dose-dependent reduction in liver thrombopoietin mRNA, suggesting that reduced GPIbα ectodomain shedding may unleash thrombopoiesis. A cluster of clinical markers, including younger age, non-alcoholic fatty liver disease, visceral obesity and higher thrombopoietin/glycocalicin ratio, predicted with significant accuracy the likelihood of faster COX-1 recovery and suboptimal aspirin response. Circulating thrombopoietin/glycocalicin ratio, reflecting a dysregulation of platelet lifespan and production, may provide a simple tool to identify patients amenable to more frequent aspirin daily dosing.