Antiplatelet properties of Pim kinase inhibition are mediated through disruption of thromboxane A2 receptor signaling

Amanda J. Unsworth*, Alexander P. Bye, Tanya Sage, Renato S. Gaspar, Nathan Eaton, Caleb Drew, Alexander Stainer, Neline Kriek, Peter J. Volberding, James L. Hutchinson, Ryan Riley, Sarah Jones, Stuart J. Mundell, Weiguo Cui, Hervé Falet, Jonathan M. Gibbins

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Pim kinases are upregulated in several forms of cancer, contributing to cell survival and tumor development, but their role in platelet function and thrombotic disease has not been explored. We report for the first time that Pim-1 kinase is expressed in human and mouse platelets. Genetic deletion or pharmacological inhibition of Pim kinase results in reduced thrombus formation but is not associated with impaired hemostasis. Attenuation of thrombus formation was found to be due to inhibition of the thromboxane A2 receptor as effects on platelet function were non-additive to inhibition caused by the cyclo-oxygenase inhibitor indomethacin or the thromboxane A2 receptor antagonist GR32191. Treatment with Pim kinase inhibitors caused reduced surface expression of the thromboxane A2 receptor and resulted in reduced responses to thromboxane A2 receptor agonists, indicating a role for Pim kinase in the regulation of thromboxane A2 receptor function. Our research identifies a novel, Pim kinase-dependent regulatory mechanism for the thromboxane A2 receptor and represents a new targeting strategy that is independent of cyclo-oxygenase-1 inhibition or direct antagonism of the thromboxane A2 receptor that, while attenuating thrombosis, does not increase bleeding.

Original languageEnglish (US)
Pages (from-to)1968-1978
Number of pages11
Issue number7
StatePublished - Jul 2021

ASJC Scopus subject areas

  • Hematology


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