# Platelet CLEC-2 in Arterial Thrombosis

> **NIH NIH R01** · OKLAHOMA MEDICAL RESEARCH FOUNDATION · 2022 · $437,000

## Abstract

PROJECT SUMMARY/ABSTRACT
 Arterial thrombotic diseases such as ischemic heart disease are the leading cause of disability and death in the
United States. Platelet adhesion and formation of thrombotic platelet aggregates at the site of a ruptured
atherosclerotic plaque or damaged endothelium under arterial blood flow is essential in the pathogenesis of arterial
thrombosis. Under high or disturbed flow conditions, the initial interaction between platelets and the vessel wall is
primarily mediated by von Willebrand factor (vWF) and platelet glycoprotein Iba (GPIba), which subsequently leads
to platelet content release, aggregation, and activation of the coagulation. These mechanisms, which are critical for
both hemostasis and thrombosis, are targets of current FDA-approved antiplatelet therapies. Although they are
effective, all have the life-threatening side effect of causing bleeding, which significantly limits their clinical use. To
address this unmet need, it is critical to further elucidate insights into mechanisms essential for thrombosis but
dispensable for hemostasis.
 Recent published data from several independent labs show that platelet CLEC-2 (C-type lectin-like receptor 2) is
important in arterial thrombosis. However, how CLEC-2 regulates arterial thrombosis is unknown. The lectin-domain
of CLEC-2 is known to bind to sialylated O-glycans. Our preliminary data showed that CLEC-2 interacts with GPIba
in a sialylation-dependent manner. Furthermore, our preliminary results reveal that CLEC-2 promotes GPIba-
mediated activation of integrin αIIbβ3, which is critical for arterial thrombus growth and stability in vivo. Importantly,
blocking CLEC-2 function does not prolong the bleeding time in vivo. Therefore, we hypothesize that CLEC-2 is
critical for GPIba-mediated platelet activation that is required for arterial thrombus growth and stability. To test this,
we will 1) test the hypothesis that CLEC-2 regulates GPIba-mediated platelet activation through interaction between
its lectin-like domain and sialylated O-glycans of GPIba as GPIba is heavily modified by sialylated O-glycans; 2)
determine if/how CLEC-2 stabilizes the arterial thrombus by facilitating GPIba-mediated integrin aIIbb3 activation using
mouse and human arterial thrombosis models.
 CLEC-2 and GPIba are expressed at similar high levels on murine platelets, and both receptors are essential in
arterial thrombosis. However, the mechanisms underlying their role in arterial thrombosis have been either elusive
(GPIba) or unknown (CLEC-2). Our proposed study will provide new mechanistic insights into these outstanding
questions in the field. It may lead to the development of a new effective and safe anti-thrombosis therapy.

## Key facts

- **NIH application ID:** 10434845
- **Project number:** 5R01HL149860-03
- **Recipient organization:** OKLAHOMA MEDICAL RESEARCH FOUNDATION
- **Principal Investigator:** Lijun Xia
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $437,000
- **Award type:** 5
- **Project period:** 2020-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10434845

## Citation

> US National Institutes of Health, RePORTER application 10434845, Platelet CLEC-2 in Arterial Thrombosis (5R01HL149860-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10434845. Licensed CC0.

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