Page 21 - Haematologica April 2020

Editorials
Using CRISPR/cas9, they created zebrafish lines carrying a null mutation in Adamts13, in VWF, and in both genes. Adamts13-/- zebrafish have higher plasma levels of VWF antigen, larger VWF multimers, and an increased ability of thrombocytes in anticoagulated zebrafish blood to adhere to a fibrillar collagen-coated surface under arterial flow. The Adamts13-/- zebrafish also show an accelerated rate of developing occlusive thrombi in the caudal venules after injury by iron chloride (FeCl3), consistent with a pro- thrombotic phenotype.29 Adamts13-/- zebrafish have a reduced number of mature and immature thrombocytes with increased erythrocyte fragmentation, suggesting a mild TTP phenotype in the basal state. The administration of a lysine-rich histone resulted in more severe and per- sistent thrombocytopenia and a mortality rate of 30% in ADAMTS13-/- versus 10% in ADAMTS13+/+ zebrafish. Both spontaneous and histone-induced TTP phenotypes in Adamts13-/- zebrafish were completely prevented when VWF was genetically deleted, proving that the pathophys- iological consequence of severe ADAMTS13 deficiency depends entirely on the presence of VWF. On the basis of these results, the zebrafish model developed by Zheng’s research team clearly recapitulates the most meaningful features of TTP, which makes this model a promising tool for in-depth exploration of the interrelations between microbes or other environmental influences and the endothelium. Besides a better understanding of the natural history of human TTP, it should also facilitate the assess- ment of novel therapeutics for TTP and possibly for other arterial thrombotic disorders. One potential limitation of this model is the phylogenetic distance between zebrafish and the human species, raising the question of whether all aspects of hemostasis involving ADAMTS13 will be com- pletely transposable to human physiology and pathology. This new zebrafish TTP model should reveal exciting and still unreported tales of TTP pathophysiology.
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