# Mechanisms of Coagulation Factor XII Recruitment and Activation at the Platelet Surface

> **NIH NIH R03** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2022 · $86,450

## Abstract

PROJECT SUMMARY
All currently available antithrombotic medications carry the risk of hemorrhage, an often
devastating complication in many patients that can rapidly reverse the benefits of therapy.
Given this reality, coagulation factor XII (FXII) has emerged as a promising new drug target that
could potentially transform antithrombotic therapy. Blockade or deletion of FXII in preclinical
animal models has consistently been shown to be protective against thrombosis, yet severe
congenital FXII deficiency is not associated with a bleeding diathesis. Therefore, inhibiting FXII
could represent the long-sought means to “decouple” hemostasis from thrombosis and achieve
antithrombotic efficacy without bleeding complications. However, despite its potential clinical
importance, little is known about the mechanisms underlying platelet-dependent FXII activation
in vivo. Using a mass spectrometry 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-integrin αIIbβ3 interaction. Our central
hypothesis is that FXII zymogen exhibits specific binding to integrin αIIbβ3 on the platelet surface,
which enhances its proteolytic activity and is necessary and sufficient for FXII-dependent
coagulation. In Aim 1 of this proposal, we will map the region(s) of FXII responsible for binding
to integrin αIIbβ3 via competitive inhibition assays using recombinantly-generated fragments of
FXII. We will also utilize surface plasmon resonance to evaluate the specificity of the FXII-
integrin αIIbβ3 interaction and obtain binding kinetics. In Aim 2, we will explore the role of integrin
αIIbβ3 binding in the activation of FXII using integrin αIIbβ3-coated beads and platelets from wild-
type and integrin β3 (ITGB3)-null mice. 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 FXII inhibition.

## Key facts

- **NIH application ID:** 10424806
- **Project number:** 1R03HL162761-01
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Pavan Bendapudi
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $86,450
- **Award type:** 1
- **Project period:** 2022-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10424806

## Citation

> US National Institutes of Health, RePORTER application 10424806, Mechanisms of Coagulation Factor XII Recruitment and Activation at the Platelet Surface (1R03HL162761-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10424806. Licensed CC0.

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