A sensitized model of thrombosis validates known multigenic relationships and suggests novel modifiers of hemostasis.

Background: Venous thromboembolism is a major cause of morbidity and mortality. Despite identification of risk factors, not all individuals with thrombophilia develop thrombosis. Understanding the multigenic factors modifying this incomplete penetrance would help guide patient care. Methods: The zebrafish has a conserved hemostatic system and is amenable to large genetic studies. Loss of antithrombin III (At3) in zebrafish leads to an early consumptive coagulopathy and lethality in adulthood. Using this genetic background as a sensitized model we performed a dominant unbiased genome-wide N-ethyl-N-nitrosourea (ENU) mutagenesis screen followed by whole genome sequencing (WGS). We used survival studies, laser-mediated endothelial injury, and Results: ENU-treated Conclusions: Unbiased genome-wide screening identified a modifier of thrombosis. This demonstrated that re-balancing of hemostasis to mitigate thrombosis is conserved in zebrafish, including an unexpected role for fibrinolysis. This interaction was not detected even in a large human dataset, establishing the continued benefit of the zebrafish model. Finally, we found evidence for novel loci outside of the canonical coagulation cascade that may be new targets for diagnosis or treatment.