Oral Presentation ESA-SRB-ANZOS 2025 in conjunction with ENSA

New generation antiplatelet agent prasugrel upregulates antioxidant and reduces anti-angiogenic pathways in primary human first trimester placenta (128438)

Natasha de Alwis 1 2 , Natalie Binder 1 , Sally Beard 1 , Lydia Baird 1 , Zoe Kodila 1 , Tu'uhevaha Kaitu'u-Lino 3 , Lisa Hui 2 4 , Natalie Hannan 1 2
  1. Department of Obstetrics, Gynaecology & Newborn Health, Therapeutics Discovery and Vascular Function in Pregnancy Group, The University of Melbourne, Melbourne, Victoria, Australia
  2. Northern Health, Epping, Melbourne, Victoria, Australia
  3. Department of Obstetrics, Gynaecology & Newborn Health, Translational Obstetrics Group, The University of Melbourne, Melbourne, Victoria, Australia
  4. Department of Obstetrics, Gynaecology & Newborn Health, The University of Melbourne, Melbourne, Victoria, Australia

Preeclampsia is a serious obstetric complication, and a leading cause of maternal and neonatal death. Aspirin, an old antiplatelet agent has been found to have limited prophylactic effectiveness. We identified that new generation antiplatelet agents, clopidogrel, prasugrel and ticagrelor mitigate key aspects of preeclampsia pathogenesis, including enhancing antioxidant cytoprotective pathways and downregulating anti-angiogenic factors in term placenta. Here, we specifically evaluate the safety of these agents in first trimester placenta, and their effect on key antioxidant and anti-angiogenic pathways in early placental development.

First trimester placental tissue was collected at surgical termination of pregnancy (6-13 weeks' gestation). Placental explants and isolated cytotrophoblast cells were treated with 100µM Aspirin, 1-100µM clopidogrel, 1-100µM prasugrel, or 0.5-25µM Ticagrelor for 48h. Cytotrophoblast viability was measured via MTS assay. Regulation of NRF2 pathway antioxidants (GCLC, HO-1, NQO1, TXN) and anti-angiogenic soluble fms-like tyrosine kinase (sFLT1) were assessed (qPCR/ELISA). Placental villous tips (2-3mm) were plated on collagen, treated for 72h, and outgrowth assessed.

Cytotrophoblast viability was unaltered with aspirin, prasugrel and ticagrelor treatment, but 100µM clopidogrel reduced cell viability (n=5; thus excluded from further studies). Prasugrel (100µM) increased NQO1 expression in explant tissue (n=4), and increased cytotrophoblast expression of GCLC, HMOX-1, NQO1, and TXN, while decreasing sFLT1 secretion (n=3). Ticagrelor reduced cytotrophoblast NQO1 expression. However aspirin, clopidogrel and ticagrelor did not alter other antioxidant genes nor sFLT1 secretion in either tissue or cytotrophoblast cells. Treatment with antiplatelet agents did not impair first trimester villous outgrowth compared to control; further studies are underway to determine whether treatment affected specific cellular proliferation, differentiation and outgrowth.

Collectively these data demonstrate prasugrel safety in early placental tissue, and its potential to enhance cytoprotective antioxidant pathways that will mitigate early placental dysfunction associated with preeclampsia. These data are essential to progressing prasugrel to clinical trials to prevent preeclampsia.