|ZFIN ID: ZDB-PUB-200307-3|
Disruption of the kringle 1 domain of prothrombin leads to late onset mortality in zebrafish
Grzegorski, S.J., Hu, Z., Liu, Y., Yu, X., Ferguson, A.C., Madarati, H., Friedmann, A.P., Reyon, D., Kim, P.Y., Kretz, C.A., Joung, J.K., Shavit, J.A.
|Source:||Scientific Reports 10: 4049 (Journal)|
|Registered Authors:||Ferguson, Allison, Grzegorski, Steven, Hu, Zhilian, Liu, Yang, Shavit, Jordan, Yu, Xinge|
|PubMed:||32132579 Full text @ Sci. Rep.|
Grzegorski, S.J., Hu, Z., Liu, Y., Yu, X., Ferguson, A.C., Madarati, H., Friedmann, A.P., Reyon, D., Kim, P.Y., Kretz, C.A., Joung, J.K., Shavit, J.A. (2020) Disruption of the kringle 1 domain of prothrombin leads to late onset mortality in zebrafish. Scientific Reports. 10:4049.
ABSTRACTThe ability to prevent blood loss in response to injury is a conserved function of all vertebrates. Complete deficiency of the central clotting enzyme prothrombin has never been observed in humans and is incompatible with postnatal life in mice, thus limiting the ability to study its role in vivo. Zebrafish are able to tolerate severe hemostatic deficiencies that are lethal in mammals. We have generated a targeted genetic deletion in the kringle 1 domain of zebrafish prothrombin. Homozygous mutant embryos develop normally into the mid-juvenile stage but demonstrate complete mortality by 2 months of age primarily due to internal hemorrhage. Mutants are unable to form occlusive venous and arterial thrombi in response to endothelial injury, a defect that was phenocopied using direct oral anticoagulants. Human prothrombin engineered with the equivalent mutation exhibits a severe reduction in secretion, thrombin generation, and fibrinogen cleavage. Together, these data demonstrate the conserved function of thrombin in zebrafish and provide insight into the role of kringle 1 in prothrombin maturation and activity. Understanding how zebrafish are able to develop normally and survive into early adulthood without thrombin activity will provide important insight into its pleiotropic functions as well as the management of patients with bleeding disorders.