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Aspirin effects on platelet gene expression are associated with a paradoxical, increase in platelet function.
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  • Rachel Myers,
  • Thomas Ortel,
  • Sandeep Dave,
  • Alexander Waldrop,
  • Geoffrey Ginsburg,
  • Deepak Voora
Rachel Myers
Duke University

Corresponding Author:[email protected]

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Thomas Ortel
Duke University
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Sandeep Dave
Duke University
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Alexander Waldrop
Duke University
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Geoffrey Ginsburg
Duke University
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Deepak Voora
Duke University
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Aspirin has known effects beyond inhibiting platelet cyclooxygenase-1 (COX1) that have been incompletely characterized. Transcriptomics can comprehensively characterize the on- and off-target effects of medications. We used a systems pharmacogenomics approach of aspirin exposure in volunteers coupled with serial platelet function and purified platelet mRNA sequencing to test the hypothesis that aspirin’s effects on the platelet transcriptome are associated with platelet function. We prospectively recruited 74 adult volunteers for a randomized cross over study of 81- vs. 325 mg/day, each for 4 weeks. Using mRNA sequencing of purified platelets collected before and after each 4-week exposure, we identified 208 aspirin-responsive genes with no evidence for dosage effects. In independent cohorts of healthy volunteers and patients with diabetes we validated aspirin’s effects on five genes: EIF2S3, CHRNB1, EPAS1, SLC9A3R2, and HLA-DRA. Functional characterization of the effects of aspirin on mRNA as well as platelet ribosomal RNA demonstrated that aspirin may act as an inhibitor of protein synthesis. Database searches for small molecules that mimicked the effects of aspirin on platelet gene expression in vitro identified aspirin but no other molecules that share aspirin’s known mechanisms of action. The effects of aspirin on platelet mRNA were correlated with higher levels of platelet function both at baseline and after aspirin exposure – an effect that counteracts aspirin’s known antiplatelet effect. In summary, this work collectively demonstrates a dose-independent effect of aspirin on the platelet transcriptome that counteracts the well-known antiplatelet effects of aspirin.
21 Jul 2021Submitted to British Journal of Clinical Pharmacology
22 Jul 2021Submission Checks Completed
22 Jul 2021Assigned to Editor
23 Jul 2021Reviewer(s) Assigned
09 Aug 2021Review(s) Completed, Editorial Evaluation Pending
16 Aug 2021Editorial Decision: Revise Major
05 Oct 20211st Revision Received
06 Oct 2021Submission Checks Completed
06 Oct 2021Assigned to Editor
06 Oct 2021Review(s) Completed, Editorial Evaluation Pending
08 Oct 2021Editorial Decision: Revise Minor
10 Oct 20212nd Revision Received
12 Oct 2021Submission Checks Completed
12 Oct 2021Assigned to Editor
12 Oct 2021Review(s) Completed, Editorial Evaluation Pending
18 Oct 2021Editorial Decision: Accept
May 2022Published in British Journal of Clinical Pharmacology volume 88 issue 5 on pages 2074-2083. 10.1111/bcp.15127