Platelet protease activated receptor 4 (PAR 4) genotype and response to aspirin in pregnancy Open Access

1. Pregnant patients homozygous for PAR4-Thr120 variant have similar response to 81mg aspirin as measured by PFA-100 epinephrine closure time

2. Despite 81mg aspirin daily, pregnant patients homozygous for PAR4-Thr120 may be at increased risk for placental intervillous thrombosis

Platelet protease activated receptor-4 (PAR4) Thr-120 allele is an activating allele associated with reduced aspirin response in-vitro. Aspirin is recommended in high-risk pregnancies to prevent preeclampsia and preterm birth. Evaluate the impact of PAR4 genotype on aspirin response in pregnancy, measured by Platelet Function Assay epinephrine closure time (PFA-100), and perinatal outcomes. Prospective cohort study of high-risk pregnancies taking 81mg aspirin daily. PFA-100 was assessed at baseline, 2-4 weeks after aspirin initiation (follow up-1) and at 28-32 weeks gestation (follow up-2). Primary outcome was difference in PFA-100 by genotype. Exposure defined as PAR4 Thr-120 homozygous vs not. 122 participants were included, 24 (19.6%) were PAR-4 Thr120 homozygous, and 106 completed follow up-1 with >75% adherence. Participants homozygous for PAR4 Thr-120 had a significantly higher rate of prior preterm birth (50.0% vs 16.1%, p=0.004). Genotype was not significantly associated with PFA-100 response in multivariable regression. In subset N=18 with urinary thromboxane data available, there was higher thromboxane levels in those homozygous vs not (geometric mean ratio 208 (1.66-2.61), p<.001in multi variable regression. There was a higher rate of placental intervillous thrombosis, not statistically significant (16.7% vs 3.9%, p=0.08). Patients homozygous for PAR-4 Thr120 had higher incidence of prior preterm birth, a risk factor for poor perinatal outcome. Aspirin response, measured by PFA-100, was similar across genotypes, although Thr120 homozygosity may be associated with reduced thromboxane suppression and a higher rate of placental vasculopathy even with 81mg aspirin daily.