# Platelet-mediated mechanisms of placental and systemic hypercoagulability in preeclampsia

> **NIH NIH K01** · UNIVERSITY OF MISSISSIPPI MED CTR · 2024 · $106,394

## Abstract

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...

## Key facts

- **NIH application ID:** 10898077
- **Project number:** 5K01HL159032-03
- **Recipient organization:** UNIVERSITY OF MISSISSIPPI MED CTR
- **Principal Investigator:** Ana Carolina Palei
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $106,394
- **Award type:** 5
- **Project period:** 2022-08-20 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10898077

## Citation

> US National Institutes of Health, RePORTER application 10898077, Platelet-mediated mechanisms of placental and systemic hypercoagulability in preeclampsia (5K01HL159032-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10898077. Licensed CC0.

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