The endothelial protein C receptor plays an essential role in the maintenance of pregnancy

Abstract

Placenta-mediated pregnancy complications are a major challenge in the management of maternal-fetal health. Maternal thrombophilia is a suspected risk factor, but the role of thrombotic processes in these complications has remained unclear. Endothelial protein C receptor (EPCR) is an anticoagulant protein highly expressed in the placenta. EPCR autoantibodies and gene variants are associated with poor pregnancy outcomes. In mice, fetal EPCR deficiency results in placental failure and in utero death. We show that inhibition of molecules involved in thrombin generation or in the activation of maternal platelets allows placental development and embryonic survival. Nonetheless, placentae exhibit venous thrombosis in uteroplacental circulation associated with neonatal death. In contrast, maternal EPCR deficiency results in clinical and histological features of placental abruption and is ameliorated with concomitant Par4 deficiency. Our findings unveil a causal link between maternal thrombophilia, uterine hemorrhage, and placental abruption and identify Par4 as a potential target of therapeutic intervention.

Illustrated State-of-the-Art Capsules of the ISTH 2023 Congress

“…TM deficiency results in a tissue-factor (TF) dependent and platelet-mediated embryonic loss in mice. Endothelial protein-C receptor (EPCR) deficiency causes mid-gestational embryonic death via integrin and PAR mediated platelet activation and neutrophil infiltration [ 18 ]. On the other hand, EPCR expressing trophoblast promotes aPL antibody mediated signaling and TNF-α release promoting systemic inflammation.…”