# Characterization of Coagulation Factor-platelet Interactions: Role of FXI

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2024 · $694,550

## Abstract

Project Summary:
Hyperlipidemia and thromboinflammation are among the unifying drivers of cardiovascular disease—the
leading cause of morbidity and mortality worldwide. Vascular inflammation results in part from lipid
accumulation within the blood vessel lumen, prompting endothelial cell dysfunction and localized loss of
endothelial barrier function. Concomitant activation of the coagulation cascade culminates in thrombin
generation, inciting platelet activation and pathological clot formation. Our work has defined the role of
coagulation factor (F)XI in propagating thrombin generation by way of both activating downstream
coagulation factors as well as proteolyzing inhibitors of thrombin generation. Yet, the crosstalk between the
coagulation cascade, FXI, and the pathways mediating inflammation and endothelial cell barrier function
remain ill-defined. We made the novel observations that the endothelium selectively inhibits activated FXI
by binding, inactivating, and internalizing FXIa. Moreover, we found that pharmacological targeting of FXI
protected endothelial barrier function in a mouse model of hyperlipidemia. In a non-human primate model
of diet-induced hyperlipidemia, our preliminary studies show that pharmacological targeting of FXI reduced
platelet sensitization and markers of inflammation including C-reactive protein (CRP). This reduction in CRP
is akin to our observations in prospective clinical trials of FXI therapeutics where we found that FXI inhibition
reduced levels of CRP in patients on dialysis or following placement of an indwelling catheter. Herein we
will define the mechanistic link between FXI activation and activity, inflammation, and endothelial cell barrier
function. This program will build on our ability to develop tools for molecular imaging of cellular functions
coupled with the creation and use of novel inhibitors of FXI and the contact pathway coagulation factors,
with a focus on translation from in silico models, in vitro studies to in vivo mouse and nonhuman primate
models. In Aim 1 we will test the hypothesis that inactivation of FXIa by endothelial cells signals to reduce
vascular endothelial barrier function. Aim 2 will focus on defining the role of FXI activation and FXIa activity
in platelet activation and thromboinflammation associated with hyperlipidemia. We will employ three
complementary mouse models and a non-human primate model of hyperlipidemia to improve rigor and
translational relevance of our results. This work will provide rationale for use of FXI inhibitors for the
treatment and prevention of thromboinflammation.

## Key facts

- **NIH application ID:** 10801503
- **Project number:** 2R01HL101972-14A1
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Owen J McCarty
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $694,550
- **Award type:** 2
- **Project period:** 2010-07-15 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10801503

## Citation

> US National Institutes of Health, RePORTER application 10801503, Characterization of Coagulation Factor-platelet Interactions: Role of FXI (2R01HL101972-14A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10801503. Licensed CC0.

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