Platelet Hyperreactivity in Early Pregnancy Tied to Ischemic Placental Disease

A distinct subset of pregnant patients—those with platelet hyperreactivity—have nearly 4-fold higher odds of developing ischemic placental disease (IPD) than those without, according to a new study in the Society for Maternal Fetal Medicine’s journal Pregnancy. IPD is a syndrome of placentally mediated obstetrical complications including hypertensive disorders of pregnancy, fetal growth restriction, and placental abruption.

“Platelets appear to be one of the primary mediators of ischemic placental disease,” says lead author Christina A. Penfield, MD, MPH, a maternal–fetal medicine subspecialist and co-director of NYU Langone’s Cardio-Obstetrics Program. “These pregnancy complications are associated with the formation of microthrombi that impair placental trophoblast invasion and contribute to placental infarcts.”

The researchers prospectively evaluated the association between first-trimester platelet hyperreactivity and development of IPD in a cohort of pregnant patients. They also investigated the role of aspirin on platelet aggregation among those with and without platelet hyperreactivity.

Dr. Penfield and colleagues found first-trimester platelet hyperreactivity was present in almost one third of pregnant patients and was independently associated with increased risk of IPD.

The POPPY study

Pregnancy Outcomes and Platelet PhenotYpes (POPPY) is a prospective observational cohort study that was led by Dr. Penfield and cardiologist Jeffrey S. Berger, MD, director of the Center for the Prevention of Cardiovascular Disease.

The study collected blood samples from pregnant participants in the first and second trimester, both before the start of aspirin therapy and after a subset of participants started aspirin 81 mg daily for preeclampsia prevention. The team then used light transmission aggregometry to examine aspirin’s effect on platelet activity, and to determine the prevalence of platelet hyperreactivity during pregnancy.

Among 61 pregnant participants, 33 percent had baseline platelet hyperreactivity. Of those with platelet hyperreactivity, 55 percent developed IPD compared to 24 percent without the phenotype, corresponding to 3.77 higher odds of IPD.

“Platelet hyperreactivity in early pregnancy may reflect a biologically distinct phenotype associated with increased IPD risk,” explains Dr. Penfield. “We are very interested in investigating this biologically prevalent subset of patients further.”

Platelet Hyperreactivity: A Biologically Distinct Subgroup

To better understand the underlying biology of this phenotype, the researchers also performed RNA sequencing to compare the platelet transcriptomes of those with and without platelet hyperreactivity.

Notably, they uncovered differential expression of pathways related to platelet activity, energy metabolism, and immune regulation—and while mechanistic studies are still ongoing—the team expects that a more nuanced understanding of these pathways may inform diagnostics and pregnancy-related ischemic complications in the near future. This insight is evident in the first trimester, when there are more therapeutic options to prevent complications.

Since many patients at risk for preeclampsia are prescribed low dose aspirin in pregnancy, POPPY evaluated how aspirin impacted platelet activity during pregnancy. In those with a hyperreactive platelet phenotype, they found higher platelet aggregation despite low dose aspirin use (24 versus 12.5 percent in those without hyperreactivity), suggesting reduced platelet inhibition with standard aspirin dosing of 81 mg daily—and calling into question the current guideline-recommended prevention strategy.

“Standard aspirin dosing may be insufficient in high-risk populations to prevent ischemic pregnancy outcomes,” says Dr. Berger, “and a more nuanced, precision-based approach to aspirin dosing may be warranted.”

Future Investigations

According to the researchers, these findings have important potential implications for pregnant patients with platelet hyperreactivity.

Although current guidelines recommend aspirin 81 mg daily after the first trimester for those at risk for preeclampsia, this approach may not provide sufficient protection in patients with a hyperreactive platelet phenotype.

“Our study was not designed to evaluate whether aspirin can mediate the clinical impact of platelet hyperreactivity,” Dr. Penfield says. “Our future investigations will examine alternative dosing strategies to optimize pregnant patients with platelet hyperreactivity.”