# Regulation of coagulation and thrombosis by C1 inhibitor

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $685,884

## Abstract

PROJECT SUMMARY
Venous thromboembolism is a leading cause of morbidity and mortality in the United States. The contact pathway
of coagulation plays an important role in the pathogenesis of venous thromboembolism. However, there are few
studies on regulation of this pathway by endogenous anticoagulants. C1 inhibitor is a multifunctional serine
protease inhibitor that functions as a major endogenous inhibitor of kallikrein, factor XII and factor XI. Patients
with a congenital deficiency in C1 inhibitor suffer from a rare episodic swelling disorder called Hereditary
Angioedema. Critically, patients with Hereditary Angioedema have evidence of increased systemic activation of
coagulation. We recently reported that Hereditary Angioedema is associated with a significantly increased risk
of venous thromboembolism in a small case-control study. Further, we have found that Hereditary Angioedema
patient plasmas support significantly increased contact pathway-mediated coagulation. Importantly, this
phenotype could be recapitulated in C1 inhibitor deficient mice that model key aspects of Hereditary
Angioedema. Our preliminary data indicates that aberrant contact pathway-mediated coagulation and enhanced
venous thrombosis observed in C1-inhibitor deficient mice can be rescued by select anticoagulant interventions.
Additional preliminary data indicates that exogenous C1 inhibitor effectively reduces contact pathway-mediated
coagulation and venous thrombosis in C1 inhibitor replete settings. Our central hypothesis is that C1 inhibitor
prevents venous thrombosis through inhibition of contact pathway-mediated coagulation. In Aim 1 of this
proposal, we will evaluate the molecular mechanism by which endogenous C1 inhibitor regulates coagulation
and venous thrombosis in mice using substrate selective C1 inhibitor variants and an arsenal of pharmacological
inhibitors. In Aim 2, we will evaluate the impact of C1INH deficiency on coagulation and thrombosis in patients
with Hereditary Angioedema using patient samples and a large-scale epidemiological dataset. In Aim 3, we will
evaluate the therapeutic potential of exogenous C1 inhibitor in mouse models of thrombosis. The work proposed
will provide new insights into the anticoagulant activity of endogenous C1 inhibitor and the potential of exogenous
C1 inhibitor to serve as a novel hemostasis sparing anticoagulant.

## Key facts

- **NIH application ID:** 10772562
- **Project number:** 1R01HL171042-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Steven P. Grover
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $685,884
- **Award type:** 1
- **Project period:** 2024-09-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10772562

## Citation

> US National Institutes of Health, RePORTER application 10772562, Regulation of coagulation and thrombosis by C1 inhibitor (1R01HL171042-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10772562. Licensed CC0.

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