# The racial disparity in platelet PAR4 signaling enhances thrombus formation

> **NIH NIH R00** · CINCINNATI CHILDRENS HOSP MED CTR · 2021 · $249,000

## Abstract

Black individuals have a higher mortality rate from coronary heart disease (CHD) than white individuals, even
after adjusting for clinical and demographic confounders. Heightened platelet reactivity is associated with an
increased risk for occlusive platelet-rich clot formation, the major cause of CHD-related mortality. Platelets from
blacks were hyperactive compared to platelets from whites in response to protease activated receptor 4 (PAR4)
stimulation even in the presence of dual antiplatelet therapy (DAPT), aspirin, and a P2Y12 receptor antagonist.
However, it remains unknown whether the racial difference in PAR4-mediated platelet activation results in an
increase in clot formation in blacks compared to whites. The long-term objective of this study is to better
understand the underlying cause of the disparity in PAR4-mediated platelet reactivity and determine
whether the difference in PAR4 activation leads to increased thrombosis in blacks relative to whites. To
this end, Aim 1 will focus on delineating the mechanism responsible for the racial difference in PAR4 signaling.
The candidate will acquire technical expertise in order to study how a polymorphism in PAR4, more common in
blacks than whites, regulates PAR4 activation (K99 phase of Aim 1). The R00 phase of Aim 1 will determine
whether differences in PAR4 activation enhance downstream signaling, and how rare PAR4 polymorphisms
influence PAR4 activation. Further, it remains unknown if the racial disparity in PAR4-mediated platelet reactivity
persists in platelets from cardiac patients on DAPT. Hence, in the K99 phase of Aim 2, patients on DAPT will be
recruited and their platelet reactivity will be assessed to determine if the racial difference in PAR4-mediated
platelet activation persists in individuals on DAPT. The R00 phase of Aim 2 will utilize a biorepository generated
during the K99 phase to determine whether blacks have an increase in basal platelet activation compared to
whites. To determine whether thrombosis differs between blacks and whites thrombus formation will be
evaluated in vivo with humanized mouse (K99 phase of Aim 3), as well as ex vivo models (R00 phase; Aim 3).
Additionally, humanized mouse models will be used to determine whether there is a racial difference in
hemostasis (R00 phase of Aim 3). A better understanding of the mechanism responsible for the racial disparity
in PAR4 signaling will provide evidence for targeted therapy to treat individuals with an increase in PAR4-
mediated platelet reactivity. Additionally, as PAR1 antagonists are currently approved and PAR4 antagonists are
in pre-clinical development, this work has important clinical implication as to which patients may benefit the most
from selective PAR inhibition. This proposal describes an intensive training plan of didactic courses, seminars,
and hands-on training that will differentiate the candidate from his mentor and allow him to develop an
independent career in platelet disparities research.

## Key facts

- **NIH application ID:** 10134406
- **Project number:** 5R00HL136784-04
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Benjamin Eric Tourdot
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $249,000
- **Award type:** 5
- **Project period:** 2020-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10134406

## Citation

> US National Institutes of Health, RePORTER application 10134406, The racial disparity in platelet PAR4 signaling enhances thrombus formation (5R00HL136784-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10134406. Licensed CC0.

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