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

    Mitchell, Joanne L, Dunster, Joanne L, Kriek, Neline, Unsworth, Amanda ORCID logoORCID: https://orcid.org/0000-0003-3809-5984, Sage, Tanya, Mohammed, Yasmin MM, Simone, Ilaria De, Taylor, Kirk A, Bye, Alexander P, Ólafsson, Geir, Brunton, Mark, Mark, Sharon, Dymott, Leanne D, Whyte, Abigail, Ruparelia, Neil, Mckenna, Charlie, Gibbins, Jonathan M and Jones, Christopher I (2023) The rate of platelet activation determines thrombus size and structure at arterial shear. Journal of Thrombosis and Haemostasis, 21 (8). pp. 2248-2259. ISSN 1538-7933

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    Background: The response of platelets to activating stimuli and pharmaceutical agents varies greatly within the normal population. Current platelet function tests measure endpoint levels of platelet activation without taking the speed at which platelets activate into account, potentially missing vital metrics to characterise platelet reactivity. Objectives: To identify variability, to agonist and between 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 that measures the rate of platelet activation over time using two 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 a central control mechanism regulates the rate of platelet response to all agonists. Conclusions: For the first time, we have shown that platelet response rate corresponds to thrombus size and structure, where 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 anti-platelet therapy, targeting high shear thrombosis without exacerbating bleeding at low shear.

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