# Mechanistic Elucidation and Targeted Therapy of Platelet Dysfunction After Trauma

> **NIH NIH R35** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $365,756

## Abstract

Project Summary: Trauma is the leading cause of death in young people worldwide and has an estimated
annual healthcare cost of 400 billion dollars per year in the United States alone. Survivors of trauma suffer
from severe morbidity in the form of organ failure and thromboembolic complications, which are driven, in large
part, by excessive inflammation and a vicious cascade of coagulation abnormalities. The lack of understanding
of the mechanisms that regulate inflammation and coagulopathy following trauma present a major international
health problem, as the lack of therapeutic targets severely limits the ability to intervene. As such,
understanding the link between trauma, inflammation and coagulopathy is the key to developing strategies to
help prevent organ failure and morbidity in the millions of annual survivors of trauma. Our lab has recently
made great strides towards understanding a potential link. We have identified that signalling through the key
innate immune receptor, toll-like receptor 4 (TLR4) on platelets is responsible, in part, for both excessive
inflammation and coagulopathy following severe hemorrhage in mice. These findings are a key early advance
in the field, as platelets serve as both the initial responders in hemostasis but also as early, key effector cells in
the initiation of inflammation. Despite these discoveries, the ligand that triggers this platelet `dysfunction'
through TLR4 is unknown. Importantly, severe trauma is known to activate the innate immune system through
a release of high quantities of danger associated molecular pattern molecules (DAMPs). The present proposal
is based on the hypothesis that high-mobility group box 1 (HMGB1), a key DAMP and well characterized TLR4
ligand, is released specifically by platelets following trauma and regulates both the coagulation abnormalities
seen after trauma by paracrine signalling on adjacent platelets at the site of developing thrombus as well as
excessive inflammation through signalling to neutrophils and other inflammatory cells. We seek to address 3
key challenges related to this hypothesis. The first involves understanding the mechanisms by which HMGB1
promotes thrombosis through examining effects on key platelet adhesion molecules. The second examines
the role of platelet HMGB1 in neutrophil activation and production of neutrophil extracellular traps (NETs)
following trauma and the role of platelet-HMGB1 mediated NET production in acute lung injury. Finally, we
propose the novel and innovative approach of using a TLR4 inhibitor that we have recently patented (US
#9,072.760) and HMGB1 inhibitors packaged into a platelet-mimicking drug delivery nanovector for specific
targeting of activated platelets at the site of inflammation and developing thrombus.

## Key facts

- **NIH application ID:** 9933936
- **Project number:** 5R35GM119526-05
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Matthew D Neal
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $365,756
- **Award type:** 5
- **Project period:** 2016-09-01 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9933936

## Citation

> US National Institutes of Health, RePORTER application 9933936, Mechanistic Elucidation and Targeted Therapy of Platelet Dysfunction After Trauma (5R35GM119526-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9933936. Licensed CC0.

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