Upon vascular challenge, hemostasis prevents excessive bleeding. The factors in blood plasma and the vascular cells which drive blood clotting and its resolution are integral to hemostasis, but they also contribute to thrombosis, where pathological clotting leads to obstructed blood flow. The mechanism that leads to the formation and dissolution of a fibrin-rich blood clot is conserved throughout vertebrates. From jawless fish to humans, prothrombin is proteolytically activated to thrombin and this catalyzes the cleavage of fibrinogen which assembles into fibrin.
While a plethora of human diseases are linked to ineffective formation or resolution of blood clots, this thesis is focused on zebrafish models of hereditary coagulopathies, or bleeding disorders, with particular emphasis on those caused by mutations in coagulation factor genes. Hereditary coagulopathies caused by known genetic variants are considered rare diseases, but still affect hundreds of thousands of patients worldwide. Work aimed at improved understanding and treatment modalities in hemostasis remain areas of intense basic and clinical research.
The zebrafish, Danio rerio, was recently adopted as a model organism for coagulation factor deficiencies. High fecundity, transparent embryogenesis, a well-annotated genome sequence, and ease of maintenance have made it a staple for biomedical research. For hemostasis, the zebrafish embryo and larvae enable rapid in vivo assessment of blood clotting without the need for surgery, a key advantage over mammalian models.
The publications included here all concern zebrafish fibrinogen. The zebrafish fibrinogen genes were characterized, an afibrinogenemia model established, and the impact of both quantitative and qualitative changes in zebrafish fibrinogen studied, showing key pathophysiological parallels with human fibrinogen disorders. Zebrafish were also used to study the effects of drugs which change fibrinogen expression on blood clotting, and to uncover the functional importance for a conserved embryonic fibrinogen isoform.
Our work, and that of others, has highlighted the usefulness of the zebrafish for hemostasis studies. The increase in genome sequencing data and improved genome editing techniques will now allow us to generate more focused zebrafish models of genomic variants implicated in diseases of hemostasis and thrombosis.
