# Tyrosine Kinases and Thrombosis

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2024 · $435,887

## Abstract

Project Summary
Tyrosine kinase inhibitors (TKIs) are important therapeutic agents to treat various cancers. However, any
agent has a tradeoff between efficacy and on or off target deleterious effects. This notion became evident in
the treatment of chronic myelogenous leukemia (CML) when a potent and broadly inhibitory tyrosine kinase
inhibitor, ponatinib (Iclusig, Ariad Pharmaceuticals, now Takeda) was recognized to have a 31% incidence of
cardiovascular (CV) events of which 21% overall were significant adverse events (SAEs). In a Phase II trial
(PACE) at 4 yrs. the incidence of arterial occlusive events was 26% (myocardial infarction 14%, stroke 11%,
and limb ischemia 11% - some patients have more than 1 organ event). Ponatinib (poni) is one of 5 TKIs
approved for the treatment of CML
We have created a murine model to examine the effects of TKIs on blood coagulation, vascular, and platelet
function. In aged mice treated with the various TKIs under steady-state conditions, ponatinib, unlike imatinib,
demonstrated an increased risk of arterial and venous thrombosis. Poni treatment leads to decreased arterial
occlusion times, larger venous clots and generates hyperactive platelets - features that contribute to
heightened thrombosis. Our laboratory has identified key mechanisms underlying the prothrombotic
phenotype of poni. First, poni-treated mice have increased vessel wall reactive oxygen species (ROS),
apoptosis, and inflammatory vascular lymphocyte infiltrates that expresses coagulation factors V and VIII.
Second, platelets from poni-treated mice are hyperactive to in response to collagen. Additionally, we have
determined that pioglitazone (pio), a PPAR agonist, when given with poni normalizes the vessel wall
inflammation and platelet hyperactivity to correct murine thrombosis risk
The overall hypothesis of this application is that poni-associated thrombosis results from immune cell vascular
inflammation expressing prothrombotic genes and altered platelet signaling resulting in platelet hyperreactivity.
Poni treatment has identified a novel mechanism of prothrombotic vascular dysfunction by which vascular
infiltrating lymphocytes express coagulation enzymes FV and FVIII potentially to contribute to thrombosis. At
therapeutic dosing in man, poni inhibits p-LynY507, a negative regulator of activated GPVI, in both unstimulated
and activated platelets with little effect on p-LynY396 and p-SykY352, suggesting that these platelets may be
more reactive. In fact, poni-treated mice have platelets that react to lower concentrations of CRP. These
defects are genetically and functionally corrected by pio’s genomic and non-genomic PPAR agonism. The
specific aims of the proposal are as follows:
The specific aims of the proposal are as follows: 1) Determine the mechanism of ponatinib- and other TKI-
induced vascular inflammation 2) Identify the mechanisms of poni-induced platelet hyperactivation.
These studies will determine the mechanisms of poni and othe...

## Key facts

- **NIH application ID:** 10772022
- **Project number:** 5R01HL157405-03
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** ALVIN H SCHMAIER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $435,887
- **Award type:** 5
- **Project period:** 2022-02-15 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10772022

## Citation

> US National Institutes of Health, RePORTER application 10772022, Tyrosine Kinases and Thrombosis (5R01HL157405-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10772022. Licensed CC0.

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