loading page

Aspirin effects on platelet gene expression are associated with a paradoxical, increase in platelet function.
  • +3
  • Rachel Myers,
  • Thomas Ortel,
  • Sandeep Dave,
  • Alexander Waldrop,
  • Geoffrey Ginsburg,
  • Deepak Voora
Rachel Myers
Duke University
Author Profile
Thomas Ortel
Duke University
Author Profile
Sandeep Dave
Duke University
Author Profile
Alexander Waldrop
Duke University
Author Profile
Geoffrey Ginsburg
Duke University
Author Profile
Deepak Voora
Duke University
Author Profile

Abstract

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.

Peer review status:IN REVISION

21 Jul 2021Submitted to British Journal of Clinical Pharmacology
22 Jul 2021Assigned to Editor
22 Jul 2021Submission Checks Completed
23 Jul 2021Reviewer(s) Assigned
09 Aug 2021Review(s) Completed, Editorial Evaluation Pending
16 Aug 2021Editorial Decision: Revise Major