# Thymidine Phosphorylase: a Novel Target of Antiplatelet Therapy

> **NIH NIH R15** · MARSHALL UNIVERSITY · 2022 · $444,000

## Abstract

Project Summary/Abstract
Platelet activation and aggregation is a major component of thrombosis, an underlying cause of myocardial
infarction, ischemic stroke, and severe COVID-19, a new viral respiratory illness caused by severe acute
respiratory syndrome coronavirus-2 (SARS-CoV-2). Various antiplatelet drugs are used clinically to prevent
thrombosis. These drugs block platelet activation and aggregation systemically and, thus, have side effects
(e.g., thrombocytopenia and hemorrhage). Therefore, new molecular mechanism-mediated antiplatelet and
antithrombotic therapies are urgently needed. We recently discovered that thymidine phosphorylase (TYMP), a
highly expressed protein in platelet cytosol, facilitates multiple agonist-induced platelet activation. TYMP
haploinsufficiency or inhibition with its inhibitors significantly attenuates arterial thrombosis without disturbing
systemic hemostasis. Most importantly, TYMP is increased in COVID-19 patients in an acuity-dependent
manner. Increased plasma TYMP in COVID-19 patients occurs earlier than the increase in C-reactive protein,
a predictive factor for inflammation and future risk of cardiovascular events. Increased TYMP is also positively
associated with plasma D-dimer and lactate dehydrogenase levels and the presence of pulmonary symptoms.
These findings indicate that TYMP may play a critical role in the development of severe COVID-19, and
modulation of TYMP activity could potentially be a systemically safe therapy against COVID-19. To this end, it
is necessary to elucidate the detailed mechanistic pathways of TYMP in platelet activation and thrombosis. We
have clarified the role of TYMP in the platelet signaling pathway mediated by platelet glycoprotein VI (GPVI).
However, we still do not know how TYMP deficiency or inhibition attenuates G-protein coupled receptor
(GPCR)-mediated platelet activation and what TYMP’s role is in the hyperthrombotic milieu of severe COVID-
19. We will address these questions in the proposed specific aims. In Aim1, we will clarify the function of TYMP
in GPCR-mediated platelet activation using specific GPCR agonists and antagonists and test the hypothesis
that a combination of low-dose TYMP inhibitor and GPCR antagonist represents a new, safe dual antiplatelet
therapy. In Aim 2, we will determine whether the SARS-CoV-2 spike protein enhances TYMP expression and
subsequent microthrombi formation in the COVID-19 milieu. We will also investigate if TYMP deficiency or
inhibition attenuates SARS-CoV-2 spike protein-associated microthrombosis and reduces mortality in mice.
Our ongoing study suggest that pharmacological inhibition of TYMP with tipiracil, a selective TYMP inhibitor
and an FDA-approved medication, is a promising anti-thrombotic therapy without bleeding disorders.
Successful completion of this R15 renewal will pave the way for repurposing tipiracil as an antiplatelet
medication for patients with high thrombotic risks, especially COVID-19 patients.

## Key facts

- **NIH application ID:** 10448031
- **Project number:** 2R15HL145573-02
- **Recipient organization:** MARSHALL UNIVERSITY
- **Principal Investigator:** Wei Li
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $444,000
- **Award type:** 2
- **Project period:** 2019-01-03 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10448031

## Citation

> US National Institutes of Health, RePORTER application 10448031, Thymidine Phosphorylase: a Novel Target of Antiplatelet Therapy (2R15HL145573-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10448031. Licensed CC0.

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