Authors:

Maya Sudhan. Lillian Smith

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Venous thromboembolism (VTE), a pathological clot formation in the venous system, is the third leading cause of cardiovascular mortality. VTE can be either acquired (e.g., from elevated estrogen levels) or inherited. Blood thinners are standard-of-care medications, but carry significant bleeding risks, highlighting the need for safer therapies. Our laboratory previously screened FDA-approved drugs in zebrafish models of VTE, leveraging zebrafish for their conserved coagulation pathway, optical transparency, and high fecundity (Yaman, Su, et al., 2025). The results identified that for estrogen-induced VTE, proton pump inhibitors (PPIs) had dual effects: nanomolar-to-micromolar concentrations increased clot formation (prothrombotic), while higher PPI levels (>5 uM) were antithrombotic (Yaman, Habiger, et al., 2025). Electronic health records reflected the prothrombotic influence, showing higher thrombosis rates in patients on PPIs and estrogen-containing contraceptives. The V-type ATPase proton pump (ATP6V) was hypothesized to mediate this effect. Complete knockouts of the catalytic subunits (afp6v1aa and atp6v1ab) led to >50% increase in thrombosis in controls, even without estrogen treatment. CRISPR-mediated knockdowns of other subunits (afp6v0c and afp6ap2) recapitulated the prothrombotic effect, emphasizing ATP6V as a major modifier of thrombosis. To explain the antithrombotic effects at higher concentrations, we hypothesize that PPls may engage with secondary targets to attenuate the prothrombotic response. At high PPI concentrations, which caused >40% reduction in estrogen-induced VTE, no abnormalities/lethality were observed, implying involvement of mechanisms besides ATP6V. Computational studies using SwissTargetPrediction suggested vascular endothelial growth factor receptors (VEGFRs) as secondary PPI targets. The effect of PPIs against estrogen-induced VTE was partially diminished in VEGFR3 knockouts, supporting a mechanistic role for VEGFR3 - investigations on other VEGFRs are pending. Our data suggest ATP6V and VEGFRs as candidate modifiers of estrogen-induced thrombosis. Further study of these may improve strategies for disease management and targeted therapies.

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Chicago Area Undergraduate Research Symposium

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Co-authors:

Maya Sudhan. Lillian Smith