Aspirin effects on platelet gene expression are associated with a paradoxical, increase in platelet function

Area of Science:

• Pharmacogenomics
• Molecular Biology
• Cardiovascular Research

Background:

• Aspirin's antiplatelet effects are primarily attributed to cyclooxygenase-1 (COX-1) inhibition.
• Additional aspirin mechanisms beyond COX-1 inhibition remain incompletely understood.
• Transcriptomics offers a comprehensive method to identify drug on- and off-target effects.

Purpose of the Study:

• To investigate aspirin's effects on the platelet transcriptome using a systems pharmacogenomics approach.
• To determine if aspirin's transcriptomic alterations correlate with platelet function.
• To test the hypothesis that aspirin's platelet transcriptome effects are dose-dependent.

Main Methods:

• A randomized crossover study involving 74 volunteers exposed to 81 mg/day and 325 mg/day aspirin for 4 weeks each.
• Purified platelet mRNA sequencing before and after each aspirin exposure.
• Validation of identified aspirin-responsive genes in independent cohorts of healthy volunteers and patients with diabetes.

Main Results:

• Identified 208 aspirin-responsive genes in platelets, with no significant dosage effects observed.
• Validated aspirin's impact on five specific genes (EIF2S3, CHRNB1, EPAS1, SLC9A3R2, HLA-DRA).
• Aspirin's effects on platelet mRNA correlated with increased platelet function, counteracting its antiplatelet action.

Conclusions:

• Aspirin exerts a dose-independent effect on the platelet transcriptome.
• Aspirin may inhibit protein synthesis in platelets.
• The observed transcriptomic changes counteract aspirin's established antiplatelet effects.