FDA-approved drug repurposing in zebrafish identifies thyroid hormone and other compounds as potential antithrombotics

ABSTRACT Venous thromboembolism (VTE) is a highly prevalent medical condition with limited therapeutic options and an incomplete understanding of its acquired and inherited subtypes. The zebrafish is a model with the benefits of external development, fecundity, optical transparency, and hemostasis that demonstrates conservation with mammals. We utilized zebrafish as a phenotypic screening tool to identify novel therapeutic options for preventing VTE. A library of FDA-approved compounds was screened for suppression of acquired (elevated estrogen) and spontaneous (protein C deficiency) thrombosis. We found that thyroid hormone, receptor tyrosine kinase (RTK) inhibitors, and proton-pump inhibitors (PPIs) effectively modulated levels of thrombosis, particularly in the estrogen-induced model. These also showed a more favorable hemostatic profile than standard therapies, suggesting alternative mechanisms. Genome editing of thyroid hormone receptor proved that thyroid hormone action is on target. A retrospective electronic health record (EHR) analysis found that thyroid-hormone prescriptions in hormonal contraceptive users correlated with a higher VTE risk, potentially limiting direct repurposing but highlighting thyroid signaling as a pathway involved in estrogen-induced thrombosis. Together, these data identify several drug classes that can be tailored to specific subtypes of VTE and help elucidate distinct pathways driving thrombosis. Competing Interest Statement J.A.S. has been a consultant for Sanofi, NovoNordisk, Biomarin, Takeda, Pfizer, Genentech, CSL Behring, and Medexus. The other authors declare no relevant conflicts of interest. Footnotes Table 2 revised; Institutional Review Board-approved Electronic Health Records identifier incorporated into Methods section; Acknowledgements section updated. https://github.com/ymnmurat/Zebrafish-Imaging-Classification