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

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 vi...

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Bibliographic Details
Published in:	Journal of thrombosis and haemostasis Vol. 21; no. 8; pp. 2248 - 2259
Main Authors:	Mitchell, Joanne L., Dunster, Joanne L., Kriek, Neline, Unsworth, Amanda J., Sage, Tanya, Mohammed, Yasmin M.M., De Simone, Ilaria, Taylor, Kirk A., Bye, Alexander P., Ólafsson, Geir, Brunton, Mark, Mark, Sharon, Dymott, Leanne D., Whyte, Abigail, Ruparelia, Neil, Mckenna, Charlie, Gibbins, Jonathan M., Jones, Christopher I.
Format:	Journal Article
Language:	English
Published:	England Elsevier Inc 01-08-2023
Subjects:	Arteries Blood Platelets - metabolism flow cytometry Humans kinetics Platelet Activation Platelet Aggregation Platelet Function Tests thrombosis Thrombosis - metabolism flow cytometry thrombosis kinetics platelet function tests platelet activation
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Summary:	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. To identify variability, to agonists and among individuals, in platelet activation kinetics and assess the impact of this on thrombus formation. 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. 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. 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. •Current platelet function tests often overlook the kinetics of platelet activation.•Real-time flow cytometry assay and analysis package measures platelet activation kinetics.•The rate of platelet activation varies considerably within the normal population.•Platelet activation rate alters thrombus size and structure at arterial, but not venous, shear.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1538-7836 1538-7836
DOI:	10.1016/j.jtha.2023.03.044