# Functional genetics of tissue factor in bleeding and thrombotic risk

> **NIH NIH DP5** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2022 · $437,500

## Abstract

Project Summary/Abstract
Tissue factor (TF) is the primary initiator of blood coagulation in vivo and is required to ensure hemostasis
following injury. However, inappropriate TF procoagulant activity underlies substantial human suffering,
including that due to myocardial infarction (MI), venous thromboembolism (VTE), stroke, and sickle cell
disease. Because the cellular contribution of TF is not captured in any routine clinical assay of blood
coagulation, the machinery influencing TF expression and procoagulant activity remains largely unknown. Our
central hypothesis is that cellular TF and its modifiers contribute to the substantial unexplained heritability of
hemostatic and thrombotic disorders, including VTE, MI, and stroke. To achieve this goal, we will intersect
functional genetic and human genetic approaches to identify modifiers that contribute to TF-dependent
heritability of bleeding and clotting risk. TF (“factor III”) is the only coagulation factor for which a hereditary
deficiency has not been described, but in Aim 1 we will study a kindred with a bleeding diathesis in association
with heterozygous TF deficiency using protein biochemistry, CRISPR-edited induced pluripotent stem cells
(iPSCs) differentiated into endothelial and vascular smooth muscle cells not accessible in humans, and
genetically modified mice via intravital microscopy following vascular injury; importantly, these efforts provide
proof of concept that modifiers reducing TF expression by 50% can influence bleeding risk in vivo. In Aim 2,
we will use an arrayed loss-of-function screen at genome-scale to identify modifiers of TF cell surface
expression and procoagulant activity and intersect these findings with expression quantitative trait loci and
existing population data capturing common and rare human genetic variation to identify areas of intersection,
offering a generalizable strategy to use a functional screen to move beyond genetic association towards
causation and mechanism. Modifiers likely contributing to TF-dependent heritability of bleeding and clotting
risk will be mechanistically evaluated at scale using a custom CRISPR array and then evaluated in iPSCs,
mice, and, where possible, humans. In Aim 3, we will study as a representative example one such discovery,
an E3 ubiquitin ligase that strongly negatively regulates TF protein stability and procoagulant activity,
employing cell biology, biochemistry, rodent models, and human genetics to mechanistically demonstrate how
human genetic variation may contribute to VTE risk. Our findings will highlight the critical but clinically
unmeasured contribution of cellular TF to the pathogenesis and inheritance of broadly defined hemorrhagic
and thrombotic diseases. The findings will have immediate translational potential for diagnostics able to
capture this risk to guide personalized treatment and suggest promise for new anticoagulant therapies with
reduced bleeding risk that selectively target pathways leading to inap...

## Key facts

- **NIH application ID:** 10488203
- **Project number:** 5DP5OD028129-04
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Sol Schulman
- **Activity code:** DP5 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $437,500
- **Award type:** 5
- **Project period:** 2019-09-16 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10488203

## Citation

> US National Institutes of Health, RePORTER application 10488203, Functional genetics of tissue factor in bleeding and thrombotic risk (5DP5OD028129-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10488203. Licensed CC0.

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