# Interdisciplinary approach to elucidate modifiers of bleeding phenotype in factor XI deficiency

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $625,071

## Abstract

PROJECT SUMMARY
Congenital deficiency of plasma clotting factor (F)XI is an autosomal disorder. Whereas some individuals are
asymptomatic (non-bleeders), others have excessive bleeding after injury, primarily at sites with high
fibrinolytic activity (mouth, nose, genitourinary tract) (bleeders). People with similarly reduced FXI have
variable bleeding even within families sharing the same FXI mutation. Clinical assays cannot predict bleeding
risk in FXI-deficient people, leading to under- or over-treatment to prevent bleeds. Moreover, FXI inhibition
strategies are in clinical trials to reduce thrombosis; however, observations of individuals with congenital FXI
deficiency suggest these therapies will incur bleeding risk in some patients, especially in prophylactic use.
Uncovering mechanisms that determine bleeding risk in FXI deficiency and developing methods to predict
bleeding will improve treatment for both bleeding and thrombosis. Our long-term goals are to characterize
mechanisms that promote hemostasis in FXI deficiency, and translate these findings into clinically-accessible
methods to predict bleeding. Using plasmas from two independent cohorts of well-phenotyped people with FXI
deficiency, we developed and validated specialized plasma assays that differentiate FXI-deficient bleeders
from non-bleeders, and discovered that inhibiting the contact pathway in these assays enhances the ability to
identify bleeders. We also integrated computational modeling and in vitro assays to uncover synergy between
FXIa and tissue factor that enhances coagulation. We built on these discoveries with new analyses that
revealed plasma proteins whose levels differed significantly between non-bleeders and bleeders, and a novel
computational workflow for advancing a prediction model. These findings and advances provide important
clues to mechanisms that modify bleeding risk in FXI deficiency, and position us with innovative tools to identify
these mechanisms. The objective of this application is to characterize the determinants and functional impact
of differently present plasma proteins in non-bleeders and bleeders, and use computational methods to
differentiate bleeding risk in FXI deficiency. The central hypothesis of this application is that in FXI deficiency,
differences in plasma composition modify thrombin generation and clot formation, structure, and stability and
determine the bleeding risk. Specific aims of this application are to: 1) Determine the functional impact and
mechanisms differentiating differently present proteins in FXI-deficient non-bleeders and bleeders, 2) Use
computational modeling and machine learning to identify predictive features that differentiate FXI-deficient non-
bleeders and bleeders, and 3) Use multi-omic methods to define FXI deficiency and the bleeding phenotype.
This proposed research is significant because the experiments will reveal molecular mechanisms that modify
hemostatic potential in a predictive functional assay and ...

## Key facts

- **NIH application ID:** 10900103
- **Project number:** 1R01HL173974-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Karin Leiderman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $625,071
- **Award type:** 1
- **Project period:** 2024-05-15 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10900103

## Citation

> US National Institutes of Health, RePORTER application 10900103, Interdisciplinary approach to elucidate modifiers of bleeding phenotype in factor XI deficiency (1R01HL173974-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10900103. Licensed CC0.

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