# Thiol Isomerases in Hemostasis and Thrombosis

> **NIH NIH R35** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2021 · $917,552

## Abstract

Project Summary
Vascular thiol isomerases modify disulfide bonds during thrombus formation in a manner
analogous to how serine proteases cleave peptide bonds. Both thiol isomerases and serine
proteases accumulate at sites of vascular injury and both are absolutely required for thrombus
formation. Yet, while our knowledge of how serine proteases contribute to coagulation is deep,
little is known about how thiol isomerases function in thrombosis. And while we have used our
knowledge of coagulation factors to develop treatments for thrombotic disease, shortcomings of
current antithrombotics in both efficacy and safety indicate a need to leverage new knowledge
of alternative mediators of thrombus formation, such as thiol isomerases, for therapeutic benefit.
We have identified novel inhibitors of protein disulfide isomerase (PDI) and have demonstrated
their efficacy in pre-clinical models. We are currently conducting a phase II/III clinical trial testing
the antithrombotic potential one of our PDI inhibitors in the setting of cancer. My research
program will focus on the role of thiol isomerases in hemostasis and thrombosis with the
objectives of determining the mechanisms by which thiol isomerases contribute to thrombus
formation and identifying disease processes in which thiol isomerase-targeted therapies could
be used therapeutically. Our studies will transform the field of thiol isomerases in hemostasis
and thrombosis by the following advances: (a) a comprehensive understanding of how vascular
thiol isomerases participate in thrombosis including how vascular thiol isomerases are
regulated, the mechanism by which they act as redox sensors, and the identification of their
substrates in thrombus formation, (b) conclusive evidence that thiol isomerases affect
hemostasis and thrombosis differently, (c) the identification of coagulopathies and thrombotic
diseases in which thiol isomerase-targeted therapies or diagnostics can be used, and (d) the
introduction of thiol isomerase-targeted reagents in clinical practice. Over the next 7 years, we
will evaluate the role of thiol isomerases in thrombosis associated with sepsis, inheritable
hypercoagulable states, anti-phospholipid syndrome, and cancer. This program will thus
address the fundamental biology of how thiol isomerases initiate thrombus formation and
identify thrombotic diseases in which they participate.

## Key facts

- **NIH application ID:** 10094223
- **Project number:** 5R35HL135775-05
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Robert C Flaumenhaft
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $917,552
- **Award type:** 5
- **Project period:** 2017-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10094223

## Citation

> US National Institutes of Health, RePORTER application 10094223, Thiol Isomerases in Hemostasis and Thrombosis (5R35HL135775-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10094223. Licensed CC0.

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