Thrombosis in the uteroplacental circulation with resultant hypoxemia and inflammation are common antecedents to intrauterine growth restriction (IUGR), fetal death, abruption and preeclampsia. These pathological obstetrical conditions are associated with acquired and inherited thrombophilias (e.g. Factor V Leiden). The goal of this application is to elucidate the biochemical mechanisms leading to uteroplacental thrombosis. Our central hypothesis is that thrombin, vascular endothelial growth factor (VEGF) and tumor necrosis factor-alpha (TNFa) aberrantly induce the potent procoagulant tissue factor (TF) in human endometrial endothelial cells (HEECs) by acting on distinct but potentially synergistic signal transduction pathways.
Three specific aims are proposed to test this hypothesis in which we will: 1) Evaluate the separate and interactive in vitro effects of thrombin, VEGF and TNFa on HEEC TF expression and determine their sites of molecular regulation. Whether adjacent stromal cells are required to mediate hypoxia-induced HEEC TF expression in pathological tissues will be assessed in a unique endothelial-stromal cell co-culture system. 2) Employ a murine model of the Factor V Leiden mutation to determine whether Inherited thrombophilia induced uteroplacental thrombosis is associated with induction of decidual endothelial cell TF and whether this is correlated with fetal and placental growth restriction. Furthermore, the pivotal role of aberrantly enhanced TF expression will be confirmed by crossbreeding mice expressing low TF levels with those carrying the Factor V Leiden mutation. 3) Conduct a prospective cohort study to determine whether increased maternal thrombin generation at various time points during human gestation and at 6-12 weeks post gestation predicts the subsequent occurrence of IUGR, abruption, preeclampsia and stillbirth. Additionally, we will correlate maternal plasma levels of two sensitive thrombin markers with the presence of acquired or inherited thrombophilias in the selected patient population.
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