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

Abstract

Background Venous thromboembolism (VTE) is a highly prevalent medical condition with limited therapeutic options, most of which carry a high risk of major bleeding. The zebrafish model, with its structural and functional homology to mammalian coagulation factors, provides a robust platform for in vivo modeling of thrombosis. Objective To identify novel therapeutic options for treating thrombosis through leveraging the zebrafish model as a phenotypic screening and in vivo efficacy model. Methods We utilized a thrombosis reporter zebrafish line with fluorescently-tagged fibrinogen to screen a library of FDA approved compounds and to phenotypically assess acquired thrombosis (increased estrogen) and spontaneous thrombosis (protein C deficiency) for validation. Candidate drugs emerging from preliminary screening were tested to compare the efficacy and safety profiles with the standard of care therapies such as warfarin, apixaban, and dabigatran. Hits were evaluated based on their structural features. Clinical relevance of the most potent candidate compounds, thyroid hormones, were evaluated through CRISPR-mediated genome editing and analyses of electronic health record (EHR) data. Results 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 (acquired) model. They also showed a more favorable hemostatic profile than standard therapies. The effectiveness of thyroid hormones was particularly notable, with functional assays indicating action through thyroid receptor signaling. EHR analyses corroborated these findings, underscoring the clinical relevance and potency of thyroid signaling modulation as a treatment target. Contrasts between the acquired and spontaneous thrombosis zebrafish models also highlighted the possibility of distinct pathological VTE subtypes. Conclusions Our findings reveal several candidate drugs as promising options for managing thrombotic disorders with tolerable bleeding risk profiles in contrast to the standard anticoagulants. Particularly, thyroid hormone signaling modulation emerges as a potential therapeutic pathway for managing estrogen-induced thrombosis. The disparities observed between the acquired and spontaneous thrombosis models highlight the need for further studies to understand the underlying mechanisms and address specific subtypes of VTE.