Impact of Protease Activated Receptor 4 Genotype on Response to Aspirin and Perinatal Outcomes in High Risk Pregnancies

Background: Platelet protease activated receptor-4 (PAR4) Thr-120 allele is an activating allele associated with increased platelet reactivity and reduced response to aspirin in vivo. We previously identified this genotype to be associated with an increased odds of preterm birth and placental vascular pathology in an unselected pregnant population. Aspirin is recommended in high risk pregnancies to prevent preeclampsia and preterm birth. It is unclear whether this genotype impacts aspirin effectiveness in pregnancy.

Objective: We aimed to compare response to aspirin, as measured by Platelet Function Assay (PFA-100) epinephrine closure time, and perinatal outcomes, by PAR-4 genotype in high risk pregnant singletons recommended 81mg aspirin daily

Methods: This is a planned secondary analysis of a prospective cohort study of N=130 high-risk singleton gestations recommended aspirin daily. As part of the primary study, participants were enrolled in the first trimester. They had PFA-100 epinephrine closure time assessed at baseline, and again 2-4 weeks after aspirin initiation (follow up-1) and finally at 28-32 weeks gestation (follow up-2). Participants were included if they had PAR-4 genotyping completed, took 81mg aspirin daily with at least 75% adherence by pill counting, and completed requisite follow up. Primary outcome was PFA-100 epinephrine closure time at follow up-1. Secondary outcomes were PFA-100 at follow up-2, incidence of hypertensive disorders of pregnancy and preterm birth, incidence of placental intervillous thrombosis. Exposure was defined as PAR4 Thr-120 homozygous vs not. Comparison was unadjusted with Mann Whitney U or chi-square, and adjusted with multivariable regression.

Results: N=122 had genotyping complete, n=24 (19.6%) were homozygous for PAR-4 Thr120. N=106 completed follow up-1 with >75% adherence. Baseline characteristics were similar except participants homozygous for PAR4 Thr-120 had a significantly higher rate of preterm birth in a prior pregnancy (50.0% vs 16.1%, p=0.004). There was no significant difference in median aspirin response at follow-up 1 in those homozygous vs not: (152.0 [80-300] vs 151[91-300] sec, p=0.90) in unadjusted or adjusted analyses. At follow-up 2 there was a non-significant reduced response: 147.3[66-300] vs 167.0 [76-300]sec, median difference -19 (-43 to 6) sec, p=0.13, and was not significant in adjusted analysis. Rates of preeclampsia and preterm birth were similar. There was a higher rate of placental intervillous thrombosis in PAR4-Thr120 homozygous, but not statistically significant (16.7% vs 3.9%, p=0.08).

Conclusion: Patients homozygous for PAR-4 Thr120 had higher incidence of prior preterm birth history, a significant risk factor for poor perinatal outcome. PFA-100 epinephrine closure time as measure of response to 81mg aspirin daily was similar across genotypes, although it is possible we were underpowered to detect a difference in the setting of other known factors (obesity, diabetes). Overall perinatal outcomes were similar, although PAR-4 Thr120 homozygous genotype may be associated with higher rate of placental vascular pathology even with daily aspirin use. Further study is needed to evaluate the role of this genotype in aspirin response, dose based response, and placental vascular pathology in high risk pregnancies.