# Resuscitation Strategies for Achieving Thrombo-inflammatory Homeostasis

> **NIH NIH RM1** · UNIVERSITY OF COLORADO DENVER · 2023 · $2,198,608

## Abstract

ABSTRACT
Annually 40,000 die of unintentional trauma in USA, from potentially preventable complications after hemorrhagic
shock. Guided damage control resuscitation (DCR) within the early golden hours improves hemostasis and
metabolic homeostasis (Gonzalez, Ann Surg. 2016; 263:1051-9). Our long term vision for this proposal is to
develop the knowledge infrastructure necessary to take DCR to the next level in 5-10 years to reduce post
traumatic morbidity and mortality drastically (25%). The objective of this RM1 is to restrict thrombo inflammation
without losing hemostasis or innate immune defense. The central hypothesis is that plasma can be tailored to
achieve thrombo-inflammatory homeostasis. Our rationale is that plasma contains soluble, innate immune
components that while perfectly normal can promote lethal thrombo-inflammation and organ injury in trauma
patients. Our specific aims test the hypotheses that Trauma and Hemorrhagic shock (T/HS) Aim 1
Resuscitating hemorrhage-induced coagulopathy and immuno-inflammation: will explore the activation of
thrombo-inflammatory serine protease cascades that increase vascular permeability, Aim 2 Allosteric
modulation of fibrinolysis mediators: multi-domain Ser-proteases (plasmin interactome): will define and
identify the released novels regulators of fibrinolysis into the plasma, Aim 3 LXR signaling and hemorrhagic
shock rapidly alter the fibrinolytic phenotype: will define the involvement of liver nuclear responses regulating
hemostasis in animals and Aim 4 Metabolic reprogramming drives deranged hemostatic and inflammatory
responses after T/HS: will characterize the metabolites that perturb innate immunity. This contribution is
significant because it provides animal and human data necessary for future FDA approvals while considering
the role of sex differences. The proposed approaches are innovative on a number of areas: First, we evaluate
complementopathy and kininopathy, which have not been well studied in the context of trauma, acidosis and
coagulopathy. Secondly, we identify new regulators of plasmin. Thirdly, the switching of fibrinolysis from one
phenotype to another through activation or antagonism of specific nuclear receptors is novel. Lastly, we have
identified a number of metabolites that are associated with and induce organ injury/dysfunction, especially lung
injury, and are investigating methods to inhibit their accumulation and effects. We have built a multidisciplinary
team to study the scope of DCR since 2010. Over the years, we have engaged and supported experts in
proteomics, metabolomics, and bioinformatics to analyze earliest patient plasma, discovering hemostatic
phenotypes that predict outcomes. We have been amongst the first to test prehospital DCR in the field, and first
to obtain detailed TEG and biochemistry of humans in post-traumatic shock. Over the years, we have refined
optimal team dynamics 1) recruiting and sustaining suitable experts, 2) assigning responsibility accord...

## Key facts

- **NIH application ID:** 10616489
- **Project number:** 5RM1GM131968-05
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Mitchell Cohen
- **Activity code:** RM1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $2,198,608
- **Award type:** 5
- **Project period:** 2019-05-20 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10616489

## Citation

> US National Institutes of Health, RePORTER application 10616489, Resuscitation Strategies for Achieving Thrombo-inflammatory Homeostasis (5RM1GM131968-05). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10616489. Licensed CC0.

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