# Development of novel anticoagulant antidotes using zebrafish

> **NIH NIH R21** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $234,000

## Abstract

PROJECT SUMMARY/ABSTRACT
Superwarfarins are 4-hydroxycoumarin derivatives that are well known to interfere with blood coagulation,
specifically through inhibition of vitamin K epoxide reductase (VKORC1), an enzyme that plays a critical role in
the recycling of vitamin K. This process is required for multiple biological systems, particularly the synthesis of
clotting factors in the liver. These toxic agents were developed in the 1970s for pest control due to increasing
warfarin resistance among rodents. They are efficacious rodenticides due to long elimination half-lives of up to
two months, but this also has led to both accidental and intentional poisonings, resulting in severe hemorrhage
and/or death. They have also been more recently discovered as contaminants of cannabinoids, leading to
clusters of hospitalizations and mortality. The only oral antidote is vitamin K, but treatment of even relatively
minor warfarin overdoses can take 24-48 hours for a substantial reduction in the risk of bleeding. Given the long
elimination half-lives of superwarfarins, weeks to months of expensive therapy is required for those agents. Major
bleeding can be urgently controlled through infusion of plasma clotting factors if they are available at the time
and place of exposure but would be scarce in mass casualty events. These also have limited shelf lives and
storage conditions and require intravenous infusion. This project will leverage highly innovative technologies,
including small molecule analysis in the zebrafish model, which has been previously shown to have a high degree
of conservation of the coagulation cascade. In preliminary studies, the research team has found that 4-
hydroxycoumarin derivatives such as brodifacoum, bromadiolone, and difenacoum, cause a profound
coagulopathy in zebrafish, which is easily and rapidly visualized in transparent embryos and larvae using
vascular endothelial injury. The proposed studies will evaluate a drug repurposing library in this model to identify
FDA-approved molecules as novel medical countermeasures for superwarfarin toxicity. This will result in the
potential rapid development of hit compounds that could expedite application to and treatment of large numbers
of affected patients.

## Key facts

- **NIH application ID:** 10848935
- **Project number:** 1R21NS137528-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Jordan A. Shavit
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $234,000
- **Award type:** 1
- **Project period:** 2024-07-09 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10848935

## Citation

> US National Institutes of Health, RePORTER application 10848935, Development of novel anticoagulant antidotes using zebrafish (1R21NS137528-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10848935. Licensed CC0.

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