PUBLICATION
Histone-induced thrombotic thrombocytopenic purpura in adamts13-/- zebrafish depends on von Willebrand factor
- Authors
- Zheng, L., Abdelgawwad, M.S., Zhang, D., Xu, L., Wei, S., Cao, W., Zheng, X.L.
- ID
- ZDB-PUB-191123-4
- Date
- 2019
- Source
- Haematologica 105(4): 1107-1119 (Journal)
- Registered Authors
- Cao, Wenjing, Zheng, Liang, Zheng, Long
- Keywords
- ADAMTS13, Inflammation, Thrombotic Thrombocytopenic Purpura, Von Willebrand factor, Zebrafish
- MeSH Terms
-
- ADAMTS13 Protein/genetics
- Animals
- Blood Platelets/metabolism
- Histones
- Purpura, Thrombotic Thrombocytopenic*/genetics
- Zebrafish/metabolism
- von Willebrand Factor/genetics
- von Willebrand Factor/metabolism
- PubMed
- 31753928 Full text @ Haematologica
Citation
Zheng, L., Abdelgawwad, M.S., Zhang, D., Xu, L., Wei, S., Cao, W., Zheng, X.L. (2019) Histone-induced thrombotic thrombocytopenic purpura in adamts13-/- zebrafish depends on von Willebrand factor. Haematologica. 105(4):1107-1119.
Abstract
Thrombotic thrombocytopenic purpura (TTP) is caused by severe deficiency of ADAMTS13 (A13), a plasma metalloprotease that cleaves endothelium-derived von Willebrand factor (VWF). However, severe A13 deficiency alone is often not sufficient to cause an acute episode; additional factors may be required to trigger the disease. Using CRISPR/Cas9, we created and characterized several novel zebrafish lines carrying a null mutation in a13-/-, vwf, and both. We further used these zebrafish lines to test the hypothesis that inflammation that results in neutrophil activation and release of histone/DNA complexes may trigger TTP. As shown, a13-/- zebrafish exhibit increased levels of plasma VWF antigen, multimer size, and ability of thrombocytes to adhere to a fibrillar collagen-coated surface under flow. The a13-/- zebrafish also show an increased rate of forming occlusive thrombi in the caudal venules after FeCl3 injury. More interestingly, a13-/- zebrafish exhibit ~30% reduction in the number of total, immature, and mature thrombocytes with increased fragmentation of erythrocytes. An administration of a lysine-rich histone results in more severe and persistent thrombocytopenia and a significantly increased mortality rate in a13-/- than in wild type (wt) zebrafish. However, both spontaneous and histone-induced TTP in a13-/- zebrafish are rescued by the deletion of vwf. These results demonstrate a potentially mechanistic link between inflammation and the onset of TTP in light of severe A13 deficiency; the novel zebrafish models of TTP may help accelerate our understandings of pathogenic mechanisms and the discoveries of novel therapeutics for TTP and perhaps other arterial thrombotic disorders. .
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping