# Molecular and genetic basis of deep venous thrombosis

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $584,332

## Abstract

Project Summary
Deep venous thrombosis (DVT) and secondary pulmonary embolism affect 0.1-0.2% of
the population and cause 60,000-100,000 deaths annually, an incidence and mortality
similar to that of myocardial infarction. In 1856 the pathologist Rudolph Virchow
implicated changes in venous blood flow in DVT pathogenesis, but a molecular and
genetic basis for how hemodynamic changes drive DVT pathogenesis has not been
identified, and present therapy is restricted to prophylactic measures to augment venous
blood flow and systemic anticoagulation. We have recently demonstrated that the
endothelial GATA2-FOXC2-PROX1 transcriptional pathway is activated by oscillatory or
reversing flow and required to stimulate the formation of venous and lymphatic valves.
Our preliminary studies demonstrate that endothelial cells around venous valves that
experience similar oscillatory flow express the GATA2-FOXC2-PROX1 transcriptional
program in association with a strong anti-coagulant phenotype marked by low vWF, high
EPCR, high TM, and high TFPI expression. Loss of this transcriptional program
conferred by altered venous flow or genetic deletion in peri-valvular ECs results in clot
formation around the venous valve. We hypothesize that endothelial GATA2-FOXC2-
PROX1 expression stimulated by oscillatory flow maintains an anticoagulant endothelial
phenotype required to prevent DVT formation. This proposal will test this hypothesis
using a combination of genetic approaches to specifically delete the
GATA2/FOXC2/PROX1 pathway in mouse peri-valvular endothelial cells, surgical
approaches to reduce venous flow in the mouse, and histologic and physiologic studies
of human venous valves to test whether this mechanism is conserved in humans and
lost during DVT pathogenesis. These studies are expected to establish a genetic and
molecular mechanism for DVT pathogenesis that will serve as the foundation for novel
mechanical and molecular therapies.

## Key facts

- **NIH application ID:** 10200879
- **Project number:** 5R01HL139552-04
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** MARK L KAHN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $584,332
- **Award type:** 5
- **Project period:** 2018-07-18 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10200879

## Citation

> US National Institutes of Health, RePORTER application 10200879, Molecular and genetic basis of deep venous thrombosis (5R01HL139552-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10200879. Licensed CC0.

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