# Trauma and Shock-Induced Microvascular Dysregulation and Coagulopathy

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2024 · $615,259

## Abstract

Program Director/Principal Investigator (Last, First, Middle): Kozar RA/ Dong JF
Project Summary
Trauma is the leading cause of preventable death, with the majority of deaths caused by hemorrhage and
associated complications due to injury to the vasculature (hemorrhagic shock [HS]). While hemorrhage results
in the rapid loss of coagulation factors and platelets, increasing evidence suggests that secondary coagulopathy
develops from a trauma-induced hypercoagulable state that rapidly turns into consumptive coagulopathy, and
is an integral part of microvascular endotheliopathy due to HS-induced hypoperfuson and tissue ischemia. The
endotheliopathy creates an inflammatory and oxidative stress environment where endothelial cells (ECs) are
activated and their barrier function disrupted. A hallmark of this microvascular dysregulation is loss of the
endothelial glycocalyx, a protective layer of carbohydrates anchored to the endothelium by syndecan-1. The
glycocalyx shields endothelial cells from blood and plasma factors and hosts anti-inflammatory, anti-thrombotic,
and anti-oxidative stress molecules. It is lost following HS with shedding of the syndecan-1 ectodomain by the
metalloprotease ADAM-17. Loss the of glycocalyx makes the anti-coagulant and anti-inflammatory endothelium
highly procoagulant and proinflammatory. The critical question is what triggers shedding and its pathological
consequences. Our recent data suggests causal roles of the adhesive ligand von Willebrand factor (VWF) and
extracellular vesicles (EVs) in endotheliopathy and coagulopathy secondary to trauma and resultant HS. In this
study, we propose to test the hypotheses that: 1) syndecan-1 shedding with progressive endothelial
dysregulation caused by release of hyperadhesive VWF and pathologic EVs, 2) syndecan-1 shedding is triggered
by clustering with ADAM-17 in membrane lipid rafts, and 3) exposure of the receptor-binding A1 domain on
hyperadhesive VWF enhances endotheliopathy by tethering inflammatory cells and EVs to the glycocalyx-
stripped endothelium. We further hypothesize that the synergistic interplay between glycocalyx loss,
hyperadhesive VWF, and EVs can be blocked to prevent endotheliopathy. We propose to test these hypotheses
by analyzing plasma samples and clinical information from trauma patients, defining pathways leading to
syndecan-1 shedding and the structural basis of VWF hyperadhesive activity in-vitro, and testing new and
innovative therapeutic strategies in mouse models of HS in the following three aims: Aim 1: To determine the
progressive microvascular dysregulation culminating in blood failure of injured patients with hemorrhagic
shock; Aim 2: To study the pathway of syndecan-1 shedding and the structure of hyperadhesive VWF in-vitro,
and Aim 3: To test new therapeutic agents to mitigate trauma-induced microvascular dysregulation in mouse
models of HS. Our proposal puts forth innovative concepts and novel mechanisms that offer a new paradigm
for the reversa...

## Key facts

- **NIH application ID:** 10765744
- **Project number:** 5R01GM140983-03
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Jing-Fei Dong
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $615,259
- **Award type:** 5
- **Project period:** 2022-03-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10765744

## Citation

> US National Institutes of Health, RePORTER application 10765744, Trauma and Shock-Induced Microvascular Dysregulation and Coagulopathy (5R01GM140983-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10765744. Licensed CC0.

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