The rate of platelet activation determines thrombus size and structure at arterial shear.

Autor:	Mitchell JL; School of Biological Sciences, University of Reading, Reading, UK; Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK., Dunster JL; School of Biological Sciences, University of Reading, Reading, UK., Kriek N; School of Biological Sciences, University of Reading, Reading, UK., Unsworth AJ; Department of Life Sciences, Manchester Metropolitan University, Manchester, UK., Sage T; School of Biological Sciences, University of Reading, Reading, UK., Mohammed YMM; School of Biological Sciences, University of Reading, Reading, UK., De Simone I; School of Biological Sciences, University of Reading, Reading, UK., Taylor KA; School of Biological Sciences, University of Reading, Reading, UK., Bye AP; Reading School of Pharmacy, University of Reading, Reading, UK., Ólafsson G; Bristol Composites Institute, Faculty of Civil, Aerospace and Mechanical Engineering, University of Bristol, Bristol, UK., Brunton M; University Department of Cardiology, Royal Berkshire Hospital, Reading, UK., Mark S; University Department of Cardiology, Royal Berkshire Hospital, Reading, UK., Dymott LD; University Department of Cardiology, Royal Berkshire Hospital, Reading, UK., Whyte A; University Department of Cardiology, Royal Berkshire Hospital, Reading, UK., Ruparelia N; School of Biological Sciences, University of Reading, Reading, UK; University Department of Cardiology, Royal Berkshire Hospital, Reading, UK., Mckenna C; University Department of Cardiology, Royal Berkshire Hospital, Reading, UK., Gibbins JM; School of Biological Sciences, University of Reading, Reading, UK., Jones CI; School of Biological Sciences, University of Reading, Reading, UK. Electronic address: c.i.jones@reading.ac.uk.
Jazyk:	angličtina
Zdroj:	Journal of thrombosis and haemostasis : JTH [J Thromb Haemost] 2023 Aug; Vol. 21 (8), pp. 2248-2259. Date of Electronic Publication: 2023 Apr 19.
DOI:	10.1016/j.jtha.2023.03.044
Abstrakt:	Background: The response of platelets to activating stimuli and pharmaceutical agents varies greatly within the normal population. Current platelet function tests are used to measure end-point levels of platelet activation without taking the speed at which platelets activate into account, potentially missing vital metrics to characterize platelet reactivity. Objectives: To identify variability, to agonists and among individuals, in platelet activation kinetics and assess the impact of this on thrombus formation. Methods: We have developed a bespoke real-time flow cytometry assay and analysis package to measure the rate of platelet activation over time using 2 parameters of platelet activation, fibrinogen binding and P-selectin exposure. Results: The rate of platelet activation varied considerably within the normal population but did not correlate with maximal platelet activation, demonstrating that platelet activation rate is a separate and novel metric to describe platelet reactivity. The relative rate of platelet response between agonists was strongly correlated, suggesting that a central control mechanism regulates the rate of platelet response to all agonists. Conclusion: For the first time, we have shown that platelet response rate corresponds to thrombus size and structure, wherein faster responders form larger, more densely packed thrombi at arterial, but crucially not venous, shear. We have demonstrated that the rate of platelet activation is an important metric in stratifying individual platelet responses and will provide a novel focus for the design and development of antiplatelet therapy, targeting high-shear thrombosis without exacerbating bleeding at low shear. Competing Interests: Funding information British Heart Foundation; Grants: PG/16/36/31967 (C.I.J. and J.M.G.) RG/20/7/34866 and RG/15/2/31224 (J.M.G and C.I.J.). European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No. 766118 (IDS). Declaration of competing interests There are no competing interests to disclose. (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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