# The Role of Coagulation Factor XII in Hemostasis and Thrombosis

> **NIH NIH K08** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2020 · $163,404

## Abstract

Project Summary/Abstract
Discovery of an antithrombotic therapy that does not cause bleeding would be a transformative advance in the
management of millions of patients with conditions such as myocardial infarction, thromboembolic disease, and
stroke who require anticoagulation but are put at risk of major hemorrhage with currently available medications.
One highly promising target is coagulation factor XII (FXII/FXIIa), based on the recent finding that mice lacking
FXII are strikingly protected from thrombosis without increased bleeding. Because it has long been known that
severe congenital FXII deficiency in humans does not cause bleeding, these results make FXII a potentially
groundbreaking antithrombotic target that could “decouple” efficacy from bleeding complications. As proof of
concept, we have shown that X210-C01, a novel therapeutic antibody against murine FXIIa, prevents arterial
thrombus formation in mice while preserving hemostasis. However, the mechanism by which FXII is recruited,
activated, and propagated during arterial thrombosis but not hemostasis remains poorly understood. Our
central hypothesis is that platelets bind and activate FXII in arterial thrombi but not in hemostatic plugs, after
which FXIIa is amplified by positive feedback via a plasma cofactor. To define the molecular mechanisms
underlying FXII function in vivo, we propose the following aims: 1) Test whether plasma kallikrein (PK) is an
essential cofactor for FXIIa in thrombus formation. We will use a novel anti-PK antibody (M202-H03) to
evaluate the effect of dual PK and FXIIa blockade on thrombus formation in vivo. We will also study the
mechanism by which PK interacts with and activates FXII. 2) Define mechanisms of FXII activation during
thrombus formation in vivo. We will test whether phosphatidylserine and platelet GPIbα are necessary and
sufficient to activate FXII at the platelet surface. We will then use intravital confocal microscopy to localize FXII
during thrombus formation. 3) Using in vivo models, test whether FXII inhibition impairs hemostasis and
determine if platelets in hemostatic plugs are phenotypically distinct from those in arterial thrombi.
 The applicant, Dr. Pavan Bendapudi, is well qualified to execute the proposed experiments. He is
committed to pursuing a scientific career in hemostasis and thrombosis and has proposed a comprehensive
five-year plan to meet his goal of becoming an independent physician-scientist. Dr. Bendapudi will be working
under the primary mentorship of Dr. Robert Flaumenhaft with Dr. Bruce Furie serving as co-mentor. He has
enlisted a research advisory committee of internationally-recognized experts in hematology to support him.
The Division of Hemostasis and Thrombosis at Beth Israel Deaconess Medical Center is an ideal environment
for completion of his scientific and career development objectives given its outstanding research community
and tradition of scientific discovery and trainee mentorship in this field.

## Key facts

- **NIH application ID:** 9960564
- **Project number:** 5K08HL136840-04
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Pavan Bendapudi
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $163,404
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9960564

## Citation

> US National Institutes of Health, RePORTER application 9960564, The Role of Coagulation Factor XII in Hemostasis and Thrombosis (5K08HL136840-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9960564. Licensed CC0.

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