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 and the potential for antithrombotic treatment have remained unclear. Endothelial Protein C Receptor (EPCR) is an anticoagulant protein highly expressed in the placenta. EPCR autoantibodies and specific gene variants of EPCR are associated with poor pregnancy outcomes. In mice, fetal EPCR deficiency results in placental failure and in utero death. Adult EPCR-deficient mice generated by maintaining placental expression exhibit plasma markers of thrombophilia without overt thrombosis. We demonstrate that inactivation of clotting factor VIII or Protease Activated Receptor 4 (Par4), Par3 or integrin IIb in the mother allows placental development and intrauterine survival of murine embryos lacking EPCR. Rescued EPCR-deficient embryos exhibit thrombosis in placental venous sinuses at late gestation and a high rate of neonatal lethality. In contrast to fetal EPCR deficiency, maternal deficiency of EPCR results in frequent stillbirths and maternal death accompanied by pathological findings that resemble placental abruption and consumptive coagulopathy. Inactivation of Par4, but not clotting factor VIII, prevents maternal death and restores normal pregnancy outcomes. These observations establish a cause-effect relationship between maternal thrombophilia and placental abruption. They demonstrate that sites of uteroplacental thrombosis and the potential response to antithrombotic intervention may differ with gestational age and maternal versus fetal origin of thrombophilia. Our findings highlight the potential for therapeutic inhibition of thrombin-mediated platelet activation in a subset of pregnancy complications. KEY POINTSO_LIMurine model establishes a cause-effect relationship between maternal thrombophilia, retroplacental hemorrhage and severe pregnancy complications. C_LIO_LIThrombin-mediated activation of maternal platelets is a key event in thrombophilia-associated pregnancy complications and a potential target of therapeutic intervention. C_LIO_LIMaternal venous channels in uteroplacental circulation are additional sites of thrombotic pathology associated with adverse neonatal outcomes. C_LI