Abstract Number: PB0142
Meeting: ISTH 2020 Congress
Background: 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; gene name Procr) 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. Adult EPCR-deficient mice generated by maintaining placental expression exhibit plasma markers of thrombophilia without overt thrombosis.
Aims: The goals of this study were to determine if maternal thrombophilia due to EPCR deficiency is associated with pregnancy complications and to test the potential for anti-platelet and anti-thrombotic therapy.
Methods: EPCR-deficient dams generated by maintaining EPCR expression in the placenta (Meox2+/creProcrlox/lox; abbreviated as Procrδ/δ) were mated to wild type C57Bl6 males and pregnancy outcomes were evaluated. We also evaluated pregnancy outcome of Par4-/-Procr-/- and FVIII-/-Procr-/- dams generated by intercrossing Par4-/-Procr+/- and FVIII-/-Procr+/- mice, respectively. Outcome studies were combined with surgical and histological evaluations.
Results: We analyzed 18 pregnancies of 12 Procrδ/δ dams. Of these, 44% resulted in maternal death or moribund mother. Mid-gestational vaginal bleeding, pregnancy loss and stillbirth were frequently observed. Surgical evaluation revealed retroplacental hemorrhaging and blanched appearance of maternal organs. The placentae appeared normally developed but blood clots were observed in the decidua basalis with infiltration of neutrophils and release of myeloperoxidase. All pregnancies of FVIII-/-Procr-/- dams resulted in maternal death (4 evaluated). In contrast, pregnancies of Par4-/-Procr-/- dams were uneventful with no observable signs of distress
Conclusions: The murine model of EPCR deficiency establishes a cause-effect relationship between maternal thrombophilia, retroplacental hemorrhage and severe pregnancy complications. It highlights the potential for therapeutic inhibition of Par4 in a subset of pregnancy complications.
To cite this abstract in AMA style:Castillo M, Solis Sigala A, Jarzembowski J, Sood R. Maternal Deficiency of Endothelial Protein C Receptor Causes Severe Pregnancy Complications Prevented by Inactivation of Protease Activated Receptor 4, but not Clotting Factor VIII [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/maternal-deficiency-of-endothelial-protein-c-receptor-causes-severe-pregnancy-complications-prevented-by-inactivation-of-protease-activated-receptor-4-but-not-clotting-factor-viii/. Accessed May 6, 2021.
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