# Biochemistry and Pathophysiology of Factor XI and Contact Activation

> **NIH NIH R35** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $790,000

## Abstract

PROJECT SUMMARY
Factor XIa (fXIa), the protease form of the plasma protein factor XI (fXI), contributes to thrombin generation
primarily by catalyzing activation of factor IX (fIX). This appears to reflect an ancillary role in the host
hemostatic response to injury, as fXI deficiency causes, at most, a relatively mild bleeding disorder. Despite its
limited role in hemostasis, mounting evidence from human population studies and animal models support the
premise that fXI contributes substantively to venous and arterial thrombosis. This has lead to considerable
interest in therapeutic inhibition of fXIa, with the hope that such a strategy will produce a useful antithrombotic
effect, with a smaller impact on hemostasis than currently used anticoagulants such as heparin, warfarin and
newer direct oral anticoagulants. FXI is structurally distinct from the vitamin K-dependent coagulation
proteases that form the core of the thrombin generation mechanism. Indeed, fXI arose from a duplication of the
gene for prekallikrein (PK), the precursor of the protease -kallikrein. PK, along with factor XII (fXII) and high
molecular weight kininogen (HK) form the kallikrein-kinin system (KKS), a component of the innate immune
response that generates proinflammatory peptides in response to injury. As a homolog of PK, fXI retains
activities of the parent molecule. However, fXI has acquired unique features that facilitate its interactions with
the thrombin generation mechanism. Our current working model is that fXI functions as a bi-directional
interface between thrombin generation and the KKS, and that this places it in a position to influence the effects
of both systems on thrombotic and inflammatory processes. Work in our laboratory is directed at establishing a
better understanding of the biochemistry, molecular biology and pathophysiology of fXI, and its relationships
with thrombin generation and the KKS. We take a broad approach to this problem, which is reflected in the
three Focus Areas described in this application. Focus Area 1 investigates important structure-function
relationships in the fXI molecule that are relevant to its activity in flowing blood. Focus Area 2 will investigate
the contributions of fXI, fXII, PK and HK to thrombus formation and sepsis in mouse models. We will also
investigate the role of fXI in modulating bleeding tendency in mice lacking factor IX (a model of hemophilia B),
and pursue a recent observation that the majority of fXI in the vasculature forms a non-circulating pool
associated with the blood vessel wall. Finally, work in Focus Area 3 is directed at a better understanding of
fXII, the precursor of a protease (fXIIa), that activates fXI and PK, and that contributes to thrombo-inflammatory
processes. We strongly feel that the expertise in our laboratory at Vanderbilt University, and the stellar group of
collaborators in academia and industry that have worked with us for over a decade, place us in a unique
position to make importa...

## Key facts

- **NIH application ID:** 9847989
- **Project number:** 5R35HL140025-03
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** David Gailani
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $790,000
- **Award type:** 5
- **Project period:** 2018-01-16 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9847989

## Citation

> US National Institutes of Health, RePORTER application 9847989, Biochemistry and Pathophysiology of Factor XI and Contact Activation (5R35HL140025-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9847989. Licensed CC0.

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