Platelet hyperreactivity and risk of ischemic placental disease: A prospective cohort study

Abstract Introduction Platelet hyperreactivity is linked to inflammation and cardiovascular risk in nonpregnant populations, but its relationship to placentally mediated pregnancy outcomes is undefined. We prospectively evaluated platelet hyperreactivity in pregnancy and subsequent ischemic placental disease (IPD), and examined aspirin's (ASA) effect on platelet activity by baseline platelet phenotype. Methods Pregnancy Outcomes and Platelet PhenotYpes (POPPY) was a prospective cohort study with blood collection in the first and second trimesters. Platelet function was assessed via light transmission aggregometry (LTA) and platelet hyperreactivity was defined a priori as >60% aggregation in response to 0.4 µM epinephrine. The primary outcome was a composite IPD endpoint (hypertensive disorders of pregnancy [HDP], placental abruption, small‐for‐gestational‐age [SGA] birth, and stillbirth). We used multivariable logistic regression to estimate the association between baseline platelet hyperreactivity and IPD. In addition, first‐trimester platelet transcriptome (pre‐ASA) was compared between participants with and without platelet hyperreactivity. In a high‐risk subset defined per US Preventative Task Force criteria and recommended ASA 81 mg daily, we evaluated ASA's effects on serum thromboxane (TxB2) and platelet aggregation by hyperreactivity status. Results Of 66 pregnant participants recruited, 61 had first‐trimester LTA; 20 (32.8%) had platelet hyperreactivity. Participants with hyperreactivity were more likely to develop IPD than those without (55% vs. 24%; adjusted odds ratio [aOR], 3.77; 95% confidence interval [CI], 1.05–13.53), with consistent directionality across individual components despite low event frequencies. Participants with platelet hyperreactivity showed greater platelet aggregation to adenosine diphosphate (ADP), collagen, and low‐dose arachidonic acid (AA). Platelet transcriptomic profiling distinguished participants with versus without platelet hyperreactivity and revealed differential expression of pathways related to platelet activity, energy metabolism, and immune regulation. Among 45 high‐risk participants recommended ASA, those with hyperreactivity exhibited higher AA‐induced aggregation (24% vs. 12.5% platelet aggregation, p = 0.01) despite similar serum TxB2 levels. Conclusion First‐trimester platelet hyperreactivity was present in approximately one third of the participants and was independently associated with increased risk of IPD. Participants with platelet hyperreactivity demonstrated distinct transcriptomic signatures and greater platelet aggregation despite ASA use. Together, these findings support a contributory role for platelets in placental ischemic pathology and highlight the need to elucidate mechanisms and develop platelet‐targeted preventive strategies. Trial Registration ClinicalTrials.gov identifier: NCT06194643.