Reduced platelet glycoprotein Ibα shedding accelerates thrombopoiesis and COX-1 recovery: implications for aspirin dosing regimen
Paola Simeone,
Rossella Liani,
Romina Tripaldi,
Sonia Ciotti,
Antonio Recchiuti,
Vittorio Abbonante,
Benedetta Porro,
Piero Del Boccio,
Augusto di Castelnuovo,
Paola Lanuti,
Marina Camera,
Damiana Pieragostino,
Melissa Lee-Sundlov,
Myriam Luongo,
Raffaella Auciello,
Giuseppina Bologna,
Maria Concetta Cufaro,
Elena Tremoli,
Karin M Hoffmeister,
Francesco Cipollone,
Alessandra Balduini,
Francesca Santilli
Affiliations
Paola Simeone
Department of Medicine and Aging Sciences, Center for Advanced Studies and Technology (CAST), University of Chieti
Rossella Liani
Department of Medicine and Aging Sciences, Center for Advanced Studies and Technology (CAST), University of Chieti
Romina Tripaldi
Department of Medicine and Aging Sciences, Center for Advanced Studies and Technology (CAST), University of Chieti
Sonia Ciotti
Department of Medicine and Aging Sciences, Center for Advanced Studies and Technology (CAST), University of Chieti
Antonio Recchiuti
Department of Medical, Oral, and Biotechnological Science, Center for Advanced Studies and Technology (CAST), Chieti
Vittorio Abbonante
Department of Molecular Medicine, University of Pavia, Pavia, Italy; Department of Health Sciences, Magna Graecia University of Catanzaro, Catanzaro
Benedetta Porro
Centro Cardiologico Monzino IRCCS, Milan
Piero Del Boccio
Department of Pharmacy, Center for Advanced Studies and Technology (CAST), Chieti
Augusto di Castelnuovo
Mediterranea Cardiocentro, Napoli
Paola Lanuti
Department of Medicine and Aging Sciences, Center for Advanced Studies and Technology (CAST), University of Chieti
Marina Camera
Centro Cardiologico Monzino IRCCS, Milan; Department of Pharmaceutical Sciences, Università degli Studi di Milano, Milan
Damiana Pieragostino
Department of Innovative Technologies in Medicine and Dentistry, Center for Advanced Studies and Technology (CAST), Chieti
Melissa Lee-Sundlov
Versiti Translational Glycomics Center and Versiti Blood Research Institute, Milwaukee, WI
Myriam Luongo
Immunotransfusion Service, Clinical Haematology of Chieti University Hospital
Raffaella Auciello
Clinical Pathology of Chieti University Hospital
Giuseppina Bologna
Department of Medicine and Aging Sciences, Center for Advanced Studies and Technology (CAST), University of Chieti
Maria Concetta Cufaro
Department of Innovative Technologies in Medicine and Dentistry, Center for Advanced Studies and Technology (CAST), Chieti
Elena Tremoli
Maria Cecilia Hospital, Cotignola
Karin M Hoffmeister
Versiti Translational Glycomics Center and Versiti Blood Research Institute, Milwaukee, WI, USA; Departments of Biochemistry and Medicine, Medical College of Wisconsin, Milwaukee, WI
Francesco Cipollone
Department of Medicine and Aging Sciences, Center for Advanced Studies and Technology (CAST), University of Chieti
Alessandra Balduini
Department of Molecular Medicine, University of Pavia, Pavia
Francesca Santilli
Department of Medicine and Aging Sciences, Center for Advanced Studies and Technology (CAST), University of Chieti
Cardiovascular (CV) disease prevention with low-dose aspirin can be less effective in patients with a faster recovery of platelet (PLT) cyclooxygenase (COX)-1 activity during the 24-hour 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 PLT glycoprotein (GP)Ibα shedding characterizes patients with accelerated COX-1 recovery and may contribute to higher thrombopoietin (TPO) production and higher rates of newly formed PLT, escaping aspirin inhibition over 24 hours. Two hundred aspirin-treated patients with high CV risk (100 with type 2 diabetes mellitus) were stratified according to the kinetics of PLT COX-1 activity recovery during the 10- to 24-hour dosing interval. Whole proteome analysis showed that PLT 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 TPO, megakaryocyte maturation and proplatelet formation, and conversely increased PLT galactose and reduced caspase 3, phosphatidylserine exposure and ADAM17 activation, translating into diminished GPIbα cleavage and glycocalicin (GC) release. Treatment of HepG2 cells with recombinant GC led to a dose-dependent reduction of TPO mRNA in the liver, 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 TPO/GC ratio, predicted with significant accuracy the likelihood of faster COX-1 recovery and suboptimal aspirin response. Circulating TPO/GC ratio, reflecting a dysregulation of PLT lifespan and production, may provide a simple tool to identify patients amenable to more frequent aspirin daily dosing.