# Thrombocytopoiesis in Diabetes:  Role of Damage Associated Molecular Patterns

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2020 · $521,355

## Abstract

Platelets play an important role in the initiation and propagation of atherosclerosis and, more so, in the ensuing
atherothrombotic complications. Although the standard antiplatelet drugs reduce the risk of atherothrombotic
complications in high-risk patients, they are not very effective in diabetes mellitus (DM) subjects. The reasons
for this remains unclear but likely due to increased production/release of reticulated platelets (RP) from the
bone marrow (BM). The RPs are immature, larger in size, hyperreactive, and less responsive to standard anti-
platelet drugs. Platelet production is tightly regulated by the hormone thrombopoietin (TPO) and its receptor, c-
MPL, which is found on several BM progenitor cells. While TPO is constitutively produced from BM stromal
cells and the kidney, the liver becomes their major source during inflammation where hepatic TPO production
is increased through the actions of interleukin-6 (IL-6). Our preliminary data suggests that hyperglycemia
enhances platelet biogenesis via mechanisms that involve neutrophil-derived S100A8/A9, a Damage
Associated Molecular Pattern (DAMP) complex, Kupffer cell (KC)-derived interleukin-6 (IL-6), and hepatic TPO.
Studies in humans have also found a positive correlation between plasma S100A8/A9, IL-6, and platelet
aggregation. Most importantly increased serum S100A8/A9 is associated with reduced anti-platelet effects of
aspirin. Based on our preliminary data and the clinical evidence, we hypothesize that hyperglycemia-induced
IL-6 production from hepatic KCs elevates plasma TPO and initiate thrombocytopoiesis resulting in higher
proportion of RPs in the blood. The newly formed RPs, being hyperreactive, enhance platelet-leukocyte
interactions and contribute to atherothrombotic complications. In order to test this hypothesis, firstly, we will
examine how glucose enhances the production of RPs in diabetes. We will specifically identify the cross talk
between circulating neutrophils and KCs by manipulating blood glucose, neutrophils, serum S100A8/A9 and
RAGE/IL6 signaling in KCs and study how these manipulations affect RP production. Secondly, we will assess
the atherogenic and thrombogenic properties of RPs in diabetes by performing various platelet function assays
both in mice and type 2 DM subjects. The findings from these studies will have a broader impact on the current
anti-platelet therapy particularly in DM subjects as there is a great potential for discovery of novel targets to
treat cardiovascular disease.

## Key facts

- **NIH application ID:** 9988608
- **Project number:** 7R01HL137799-03
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Prabhakara Reddy Nagareddy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $521,355
- **Award type:** 7
- **Project period:** 2018-04-23 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9988608

## Citation

> US National Institutes of Health, RePORTER application 9988608, Thrombocytopoiesis in Diabetes:  Role of Damage Associated Molecular Patterns (7R01HL137799-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9988608. Licensed CC0.

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