FDA-approved drug repurposing in zebrafish identifies thyroid hormone and other compounds as potential antithrombotics
Yaman, M.; Su, H.; Lee, J. K.; Ferguson, A. C.; Sowell, K. M.; Xun, J.; Wu, D.; Habiger, C. J.; Hanauer, D. A.; Clasby, M. C.; Rech, J. C.; Shavit, J. A.
Show 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.
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