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Thromb Haemost 2022; 122(07): 1130-1138
DOI: 10.1055/a-1711-1395
Cellular Haemostasis and Platelets

The PAR4 Platelet Thrombin Receptor Variant rs773902 does not Impact the Incidence of Thrombotic or Bleeding Events in a Healthy Older Population

Maria V. Selvadurai   *
1   Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, Australia
,
Moeen Riaz   *
2   Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
,
Sophia Xie
2   Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
,
Andrew M. Tonkin
2   Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
,
John J. McNeil
2   Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
,
Paul Lacaze   **
2   Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
,
Justin R. Hamilton    **
1   Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, Australia
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Abstract

Background Protease-activated receptor 4 (PAR4) is a platelet thrombin receptor important for thrombosis and a target of antiplatelet drug development. A frequently occurring single-nucleotide polymorphism (rs773902) causes a PAR4 sequence variant (NC_000019.10:p.Ala120Thr) whereby platelets from Thr120-expressing individuals are hyperresponsive to PAR4 agonists versus platelets from Ala120-expressing individuals. However, whether this enhanced platelet responsiveness translates to increased thrombotic risk or decreased bleeding risk remains unknown.

Objectives This article examines the association of rs773902 with adjudicated cardiovascular events and aspirin use in a randomized trial population of healthy older individuals.

Methods We analyzed 13,547 participants in the ASPirin in Reducing Events in the Elderly trial. Participants had no previous cardiovascular events at enrollment and were randomized to either 100 mg daily aspirin or placebo for a median follow-up of 4.7 years. Total genotypes were 8,761 (65%) GG (Ala120 variant), 4,303 (32%) heterozygotes, and 483 (4%) AA (Thr120 variant). Cox proportional hazard regression tested the relationship between rs773902 and thrombotic events (major adverse cardiovascular events [MACE] and ischemic stroke [IS]) and bleeding (major hemorrhage [MHEM] and intracranial bleeding [ICB]).

Results No statistically significant association was observed overall or by treatment group between rs773902 and any thrombotic or bleeding event examined. Further, there was no significant interaction between rs773902 and treatment for any of MACE, IS, MHEM, or ICB.

Conclusion This post hoc analysis of a prospective cohort study suggests that, despite sensitizing platelet activation, the rs773902 PAR4 variant is not associated with thrombotic cardiovascular or bleeding events in a healthy older population.

Keywords

platelets - thrombosis - hemostasis - protease-activated receptors - thrombin

Author Contributions

M.R. and S.X. analyzed data; A.M.T., J.J.M., and P.L. designed research; M.V.S. and J.R.H. designed research, analyzed data, and wrote the manuscript.


* Joint first authors.


** Joint senior authors.




Publication History

Received: 12 August 2021

Accepted: 24 November 2021

Accepted Manuscript online:
01 December 2021

Article published online:
20 January 2022

© 2022. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

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