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

Joanne L. Mitchell, Joanne L. Dunster, Neline Kriek, Amanda J. Unsworth, Tanya Sage, Yasmin M.M. Mohammed, Ilaria De Simone, Kirk A. Taylor, Alexander P. Bye, Geir Ólafsson, Mark Brunton, Sharon Mark, Leanne D. Dymott, Abigail Whyte, Neil Ruparelia, Charlie Mckenna, Jonathan M. Gibbins, Christopher I. Jones*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

3 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)2248-2259
Number of pages12
JournalJournal of Thrombosis and Haemostasis
Volume21
Issue number8
Early online date19 Apr 2023
DOIs
Publication statusPublished - 1 Aug 2023

Bibliographical note

Funding Information:
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).

Funding Information:
The authors thank the Hugh Sinclair Unit of Human Nutrition for study support and the use of their facilities. J.L.M. designed the research, performed experiments, analyzed data, and wrote the manuscript. J.L.D. designed the analysis package, wrote the analysis software, analyzed data, and wrote the manuscript. A.J.U. performed experiments, analyzed data, and edited the manuscript. N.K. performed experiments, analyzed data, and edited the manuscript. T.S. performed experiments and analyzed data. Y.M.M.M. performed experiments and analyzed data. I.D.S. performed experiments and analyzed data. A.P.B. performed experiments and analyzed data. K.A.T. performed experiments, analyzed data, and edited the manuscript. G.Ó. analyzed data and edited the manuscript. M.B. S.M. L.D.D. A.W. N.R. and C.M. designed the patient study, recruited patients, and collected patient samples. J.M.G. designed elements, analyzed data, and edited the manuscript. C.I.J. designed the research, designed the analysis package, analyzed data, and wrote the manuscript. 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). There are no competing interests to disclose. 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).

Publisher Copyright:
© 2023 The Author(s)

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