# Novel functions of Thrombin Activatable Fibrinolysis Inhibitor (TAFI)

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2022 · $651,425

## Abstract

Project Summary/Abstract
This application seeks to define new physiological functions for the plasma procarboxypeptidase B, Thrombin-
Activatable Fibrinolysis Inhibitor (TAFI). Activated TAFI (TAFIa) is a multifunctional carboxypeptidase with
various governing functions in the regulation of fibrinolytic, complement, and inflammatory pathways. Defective
activation of TAFI in hemophilia plasma in vitro has been recognized long ago, but we have only recently been
able to demonstrate that TAFI activation in hemophilia mice in vivo is also defective. Thus, hemophilia, which is
a genetic deficiency of coagulation factor VIII or IX, provides a clinically relevant condition to improve our
understanding of the (patho)physiological consequences of TAFI deficiency, since a genetic deficiency of TAFI
in humans has not yet been found. Bleeding in patients with hemophilia is characterized by a striking
susceptibility for repeated and perpetuated intra-articular bleeding in weight-bearing joints that progresses to
debilitating hemophilic arthropathy. The majority of the world’s hemophilia population does not have access to a
rigorous supply of clotting factor products for prophylactic treatment and as a result hemophilic arthropathy is
and will remain highly prevalent in the adult hemophilia population for many generations to come. Furthermore,
initiating clotting factor prophylaxis later in life does not diminish existing hemophilic arthropathy, indicating that
new knowledge for mechanisms of hemophilic joint disease (HJD), that may lead to additional therapeutic options
for patients with hemophilia and arthropathy, are urgently needed. Arthropathic joints in patients with hemophilia
are characterized by pronounced vascular abnormalities due to excessive vascular remodeling. Our work has
identified that the defective activation of TAFI drives the vascular abnormalities associated with HJD in mice after
joint bleeding. Furthermore, the vascular changes in the joint after bleeding due to the loss of TAFI function are
not explained by a loss of TAFI’s antifibrinolytic activity, suggesting that other mechanisms and substrates for
TAFI are involved. The proposed studies will test a comprehensive conceptual model aimed at obtaining basic
and translational knowledge for the benefit of patients with hemophilia and arthropathy. Our novel hypotheses
focus on the loss of attenuation of vascular endothelial growth factor A (VEGF-A) and stromal cell-derived factor-
1α (SDF-1α/CXCL12)) activity by TAFIa as driving forces behind the development of vascular abnormalities in
HJD. Three Specific Aims will guide our experimentation. New knowledge as to how a loss of TAFI function
contributes to HJD will be the focus of Aim 1. Studies of Aim 2 will test the ability of TAFIa to attenuate VEGF-A
activity and how this relates to HJD. Aim 3 is focused on the regulation of SDF-1α activity by TAFIa and the
extent to which targeting SDF-1α signaling receptors can prevent and reverse HJD...

## Key facts

- **NIH application ID:** 10378545
- **Project number:** 5R01HL148096-03
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Laurent Olivier Mosnier
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $651,425
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10378545

## Citation

> US National Institutes of Health, RePORTER application 10378545, Novel functions of Thrombin Activatable Fibrinolysis Inhibitor (TAFI) (5R01HL148096-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10378545. Licensed CC0.

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