Effects of aspirin on platelet gene expression and platelet
function outcomes
To test the hypothesis that aspirin’s effects on platelet mRNA
correlates with aspirin’s effects on non-COX1 dependent platelet
function we first summarized the overall behavior of the 51,
prioritized, differentially expressed genes identified in the Discovery
cohort into a single AES score (see Methods). By definition, the AES
score increases in response to aspirin exposure with no dosage effects
(Figure 4A). We used the aggregate AES to correlate with platelet
function scores across all cohorts (Discovery and both Validation) to
test for the relationship between the effects of aspirin on gene
expression and platelet function.
At baseline, prior to aspirin exposure, platelets with higher AES scores
can be thought of as having an endogenous “aspirin-like” effect in
their platelet transcriptomes. Prior to aspirin exposure, higher AES
scores correlated with higher PFS both before (effect = 0.49, 95%
confidence interval [CI]: 0.10-0.89, random effect model p-value =
0.01, Figure 4B and 4D) with higher levels of platelet function. In
aspirin treated samples, higher AES levels reflect those participants in
whom aspirin exposure resulted in a higher AES levels (due to higher
baseline or change upon aspirin exposure). After aspirin exposure,
higher AES levels were similarly correlated with higher platelet
function (effect = 0.70, 95% confidence interval [CI]: 0.30-1.18,
random effect model p-value = 0.002, Figure 4C and 4E). Therefore, the
biological pathways impacted by aspirin and quantified through platelet
gene expression profiling indicate that aspirin produces a paradoxical
effect that increases platelet aggregation ex vivo . Higher
aspirin-like effects (i.e., higher AES scores) either at baseline or in
response to aspirin exposure, in aggregate, correlate with higher PFS
scores, an effect that is opposite in direction with aspirin’s known
effects on inhibiting platelet COX-1 and platelet function.