Boelig Rupsa C, Michael James V, Tawk Antonios, Zhan Tingting, Chan Joanna S Y, Kraft Walter K, McKenzie Steven E
Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA.
Department of Pharmacology, Physiology, and Cancer Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA.
Blood Vessel Thromb Hemost. 2025 Jun 30;2(3):100085. doi: 10.1016/j.bvth.2025.100085. eCollection 2025 Aug.
The platelet protease-activated receptor 4 (PAR4) threonine 120 (Thr120) 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. We evaluated the impact of PAR4 genotype on aspirin response in pregnancy, as measured by platelet function assay 100 (PFA-100) epinephrine closure time, and perinatal outcomes. We conducted a prospective cohort study of high-risk pregnant patients who took 81-mg aspirin daily. PFA-100 was assessed at baseline, 2 to 4 weeks after aspirin initiation (follow-up 1), and 28 to 32 weeks' gestation (follow-up 2). Primary outcome was difference in PFA-100 by genotype. Exposure was defined as PAR4-Thr120 homozygous vs not. Of the 122 participants were included, 24 (19.6%) were PAR4-Thr120 homozygous, and 106 completed follow-up 1 with >75% adherence. Participants homozygous for PAR4-Thr120 had a significantly higher rate of prior preterm birth (50.0% vs 16.1%; = .004). Genotype was not significantly associated with PFA-100 response in multivariable regression. In the subset with urinary thromboxane data available (n = 18), thromboxane levels were higher in those who were homozygous vs not (geometric mean ratio, 208 [95% confidence interval, 1.66-2.61]; < .001) in multivariable regression. There was a higher rate of placental intervillous thrombosis, although not statistically significant (16.7% vs 3.9%; = .08). Patients homozygous for PAR4-Thr120 had a 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 81-mg aspirin daily.
血小板蛋白酶激活受体4（PAR4）苏氨酸120（Thr120）等位基因是一种激活等位基因，在体外与阿司匹林反应性降低相关。高危妊娠中推荐使用阿司匹林来预防子痫前期和早产。我们通过血小板功能分析100（PFA - 100）肾上腺素封闭时间评估了PAR4基因型对妊娠中阿司匹林反应性的影响以及围产期结局。我们对每日服用81毫克阿司匹林的高危妊娠患者进行了一项前瞻性队列研究。在基线、开始服用阿司匹林后2至4周（随访1）以及妊娠28至32周（随访2）时评估PFA - 100。主要结局是不同基因型之间PFA - 100的差异。暴露定义为PAR4 - Thr120纯合子与非纯合子。纳入的122名参与者中，24名（19.6%）为PAR4 - Thr120纯合子，106名完成了随访1且依从性>75%。PAR4 - Thr120纯合子参与者既往早产率显著更高（50.0%对16.1%；P = .004）。在多变量回归中，基因型与PFA - 100反应无显著关联。在可获得尿血栓素数据的亚组（n = 18）中，多变量回归显示纯合子的血栓素水平高于非纯合子（几何平均比值，2.08 [95%置信区间，1.66 - 2.61]；P < .001）。胎盘绒毛间隙血栓形成率更高，尽管无统计学意义（16.7%对3.9%；P = .08）。PAR4 - Thr120纯合子患者既往早产发生率更高，这是围产期不良结局的一个危险因素。通过PFA - 100测量的阿司匹林反应性在各基因型间相似，尽管即使每日服用81毫克阿司匹林，Thr120纯合性可能与血栓素抑制降低及胎盘血管病变发生率更高有关。
