# Coagulation Factor XII Recruitment and Activation During Thrombus Formation

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2024 · $685,969

## Abstract

PROJECT SUMMARY
An antithrombotic medication not associated with increased hemorrhage would be a transformative advance in
the treatment of coagulation disorders. Inhibiting coagulation factor XII (FXII) has emerged as a therapeutic
strategy that could “decouple” hemostasis from thrombosis to achieve antithrombotic efficacy without bleeding
complications. Enthusiasm for FXII as a therapeutic target stems from the observation that severe congenital
FXII deficiency is not associated with a bleeding diathesis while blockade or deletion of FXII in preclinical models
consistently protects against thrombosis. However, despite its potential clinical importance, the mechanisms
underlying platelet-dependent FXII activation in vivo remain unclear. Using a mass spectrometry-based
proteomic screen, we have identified integrin αIIbβ3 as the putative platelet receptor for FXII. These results have
been followed up with a number of additional studies reproducibly demonstrating the FXII-αIIbβ3 interaction and
localizing the integrin binding region to the kringle domain (KD) of the FXII heavy chain. Our central hypothesis
is that binding of FXII zymogen to platelet integrin αIIbβ3 potentiates FXII activation and is necessary and sufficient
for FXII-mediated coagulation. In Aim 1 of this proposal, we will map the region(s) of the FXII KD responsible
for binding to αIIbβ3 via competitive inhibition assays using recombinantly-generated fragments of the KD. We
will also evaluate the role of the FXII KD in a mouse model of thrombosis to determine if loss of the KD can
prevent thrombus formation in vivo. In Aim 2, we will work closely with our collaborators to conduct precision
structural studies of the FXII-αIIbβ3 complex. In Aim 3, we will focus on the mechanisms by which FXII binding
to αIIbβ3 leads to activation of FXII and downstream coagulation. The proposed work will provide important new
insights into the molecular mechanism of FXII recruitment, activation, and propagation at the platelet surface
and inform efforts to develop novel therapeutics based on inhibition of the FXII-αIIbβ3 complex.

## Key facts

- **NIH application ID:** 10914894
- **Project number:** 5R01HL166246-02
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Pavan Bendapudi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $685,969
- **Award type:** 5
- **Project period:** 2023-09-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10914894

## Citation

> US National Institutes of Health, RePORTER application 10914894, Coagulation Factor XII Recruitment and Activation During Thrombus Formation (5R01HL166246-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10914894. Licensed CC0.

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