Platelet-mediated mechanisms of placental and systemic hypercoagulability in preeclampsia

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PROJECT SUMMARY/ABSTRACT Preeclampsia (PE) remains a significant clinical and public health burden affecting 3-5% of all pregnancies worldwide, and is a leading cause of maternal and perinatal morbidity and mortality. Currently, there is no effective therapy for PE other than delivery. While its etiology is not fully clear, compelling evidence demonstrates that placental hypoxia/ischemia is a key initiating event that triggers the release of anti-angiogenic factors into maternal circulation, such as soluble fms-like tyrosine kinase-1 (sFLT-1) and endoglin (sEng). These placental factors cause systemic vascular dysfunction and ultimately the clinical symptoms of PE. Furthermore, PE is a well-established hypercoagulable state, associated with placental thrombosis as well as increased risk for thrombotic events during and after pregnancy. Hypercoagulability could contribute to exaggerated placental disease and systemic vascular dysfunction in PE. Although increased expression of procoagulant factors and platelet activity along with decreased anticoagulant activity have been implicated in this prothrombotic tendency, the precise mechanism underlying hypercoagulability in PE remain to be fully elucidated. Extracellular mitochondrial DNA (mtDNA), a damage-associated molecular pattern released from hypoxic and/or injured tissue, is known to directly activate platelets, triggering reactive oxygen species overproduction by their mitochondria, which in turn leads to apoptosis and release of additional mtDNA from platelets. This this feed- forward cycle results in escalating platelet activation and hypercoagulability that culminate in thrombosis remote from the initial site of mtDNA release. While placental and maternal mtDNA levels are elevated in PE patients, its role as a mediator of hypercoagulability in the placental and systemic circulation during PE has never been investigated. Moreover, circulating mtDNA can be directly depleted by DNase I treatment, which has been shown to inhibit in vitro and in vivo platelet activation and aggregation. However, DNase I has never been explored as a therapy for PE. To address this knowledge gap, we propose to examine whether mtDNA acts as a driver of hypercoagulability in the placental and systemic circulation during PE, and whether this effect can be mitigated by DNase I treatment using the rat sFLT-1/sEng model of severe PE. Similar to severe preeclamptic patients, the chronic sFLT-1 and sEng infusion into pregnant rats promotes placental pathology, hypertension, reduced platelet counts, and end-organ damage. Parallel ex vivo studies will determine whether sFLT-1, sEng, and placental mtDNA cause platelet activation, mitochondrial dysfunction, and aggregation. Thus, by applying integrative novel approaches, clinically relevant models of PE, and advanced methodologies, we will test the central hypothesis that mtDNA mediates platelet activation, mitochondrial dysfunction, hypercoagulability, and vascular dysfunction in severe PE, and that this pathway is ameliorated by DNase I treatment. Findings generated by these groundbreaking studies could revolutionize the standard of care for PE by identifying a novel class of mtDNA-targeted antithrombotic agents with potential wide applicability to other hypercoagulable states.