Page 276 - Haematologica April 2020

L. Zheng et al.
This prevents excessive thrombus formation at the sites of vascular injury; when plasma A13 activity is absent, the released ULVWF remain anchored on the endothelial sur- face, which can capture flowing platelets in circulation, resulting in occlusive thrombi and acute inflammation at the sites of vascular injury. This creates a positive feed- back, resulting in more inflammation and cell death, which leads to the formation of a vicious cycle (Figure 8).
In conclusion, we report the generation and characteri- zation of several novel zebrafish lines (a13-/-, vwf-/-, and a13-/-vwf-/-) and zebrafish models of TTP. With these new tools, we are able to demonstrate potentially mechanistic links between infection, innate immunity (such as neu- trophil activation and the release of histone/DNA com- plexes), and the onset and progression of TTP in the set- ting of severe deficiency of plasma A13 activity. These novel zebrafish models with a robust high-throughput screening capability could help accelerate the discovery of
potentially novel therapeutics for TTP and many other arterial thrombotic disorders, in which treatment options are quite limited.
Acknowledgments
This study was supported in part by a grant from the National Institutes of Health (HL126724) to XLZ and a postdoctoral fel- lowship (18POST33960098) to LZ from the American Heart Association. The authors also thank Drs. Daniel Gorelick and Shannon Romano from the Department of Pharmacology and Toxicology at UAB for providing a double transgenic zebrafish line expressing fli-1eGFP and gata-1dsRed, Dr. Susan Farmer at the Zebrafish Research Facility for providing wildtype zebrafish, and Drs. Robert I. Handin and Dongdong Ma, at Harvard Medical School, Boston, MA for helping us with the cd41-mCherry transgenic zebrafish line. The authors thank Nicole Kocher at UAB for her assistance and critical reading of this paper prior to its submission.
References
1. ZhengXL.ADAMTS13andvonWillebrand factor in thrombotic thrombocytopenic pur- pura Annu Rev Med. 2015;66:211-225.
2. Rock GA, Shumak KH, Buskard NA, et al. Comparison of plasma exchange with plas- ma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group. N Engl J Med. 1991;325(6):393-397.
3. Tsai HM, Lian EC. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Eng J Med. 1998;339(22):1585-1594.
4. ZhengXL,WuHM,ShangD,etal.Multiple domains of ADAMTS13 are targeted by autoantibodies against ADAMTS13 in patients with acquired idiopathic thrombot- ic thrombocytopenic purpura. Haematologica. 2010;95(9):1555-1562.
5. Ostertag EM, Bdeir K, Kacir S, et al. ADAMTS13 autoantibodies cloned from patients with acquired thrombotic thrombo- cytopenic purpura: 2. Pathogenicity in an animal model. Transfusion. 2016;56(7): 1775-1785.
6. CasinaVC,HuW,MaoJH,etal.High-reso- lution epitope mapping by HX MS reveals the pathogenic mechanism and a possible therapy for autoimmune TTP syndrome. Proc Natl Acad Sci U S A. 2015;112(31): 9620-9625.
7. Thomas MR, de Groot R, Scully MA, Crawley JT. Pathogenicity of anti- ADAMTS13 autoantibodies in acquired thrombotic thrombocytopenic purpura. EBioMedicine. 2015;2(8):942-952.
8. Levy GG, Nichols WC, Lian EC, et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocy- topenic purpura. Nature. 2001;413(6855): 488-494.
9. ZhengXL,SadlerJE.Pathogenesisofthrom- botic microangiopathies. Annu Rev Pathol. 2008;3:249-277.
10. UemuraM,TatsumiK,MatsumotoM,etal. Localization of ADAMTS13 to the stellate cells of human liver. Blood. 2005;106(3):922- 924.
11. Zhou W, Inada M, Lee TP, et al. ADAMTS13 is expressed in hepatic stellate cells. Lab Invest. 2005;85(6):780-788.
12. Dong JF, Moake JL, Nolasco L, et al. ADAMTS-13 rapidly cleaves newly secreted ultralarge von Willebrand factor multimers on the endothelial surface under flowing conditions. Blood. 2002;100(12):4033-4039.
13. Sadler JE. von Willebrand factor: two sides of a coin. J Thromb Haemost. 2005;3(8):1702-1709.
14. Chauhan AK, Kisucka J, Brill A, et al. ADAMTS13: a new link between thrombo- sis and inflammation. J Exp Med. 2008;205(9):2065-2074.
15. De Meyer SF, Savchenko AS, Haas MS, et al. Protective anti-inflammatory effect of ADAMTS13 on myocardial ischemia/reper- fusion injury in mice. Blood. 2012;120(26):5217-5223.
16. Arya M, Anvari B, Romo GM, et al. Ultralarge multimers of von Willebrand fac- tor form spontaneous high-strength bonds with the platelet glycoprotein Ib-IX com- plex: studies using optical tweezers. Blood. 2002;99(11):3971-3977.
17. Ghosh A, Vo A, Twiss BK, et al. Characterization of zebrafish von Willebrand factor reveals conservation of domain structure, multimerization, and intracellular storage. Adv Hematol. 2012;2012:214209.
18. Jin SY, Skipwith CG, Zheng XL. Amino acid residues Arg(659), Arg(660), and Tyr(661) in the spacer domain of ADAMTS13 are criti- cal for cleavage of von Willebrand factor. Blood. 2010;115(11):2300-2310.
19. Fujimura Y, Kokame K, Yagi H, et al. Hereditary deficiency of ADAMTS13 activ- ity: Upshaw-Schulman syndrome. In: Rodgers GM, ed. ADAMTS13 Biology and Disease. Cham, Heidlberg, New York, Dordrecht, London: Springer. 2015:73-90.
20. Fujimura Y, Matsumoto M, Isonishi A, et al. Natural history of Upshaw-Schulman syn- drome based on ADAMTS13 gene analysis in Japan. J Thromb Haemost. 2011;9 Suppl 1:283-301.
21. Motto DG, Chauhan AK, Zhu G, et al. Shigatoxin triggers thrombotic thrombocy-
topenic purpura in genetically susceptible ADAMTS13-deficient mice. J Clin Invest. 2005;115(10):2752-2761.
22. Jin SY, Xiao J, Bao J, et al. AAV-mediated expression of an ADAMTS13 variant pre- vents shigatoxin-induced thrombotic throm- bocytopenic purpura. Blood. 2013;121(19): 3825-3829.
23. Schiviz A, Wuersch K, Piskernik C, et al. A new mouse model mimicking thrombotic thrombocytopenic purpura: correction of symptoms by recombinant human ADAMTS13. Blood. 2012;119(25):6128- 6135.
24. Pickens B, Mao Y, Li D, et al. Platelet-deliv- ered ADAMTS13 inhibits arterial thrombo- sis and prevents thrombotic thrombocy- topenic purpura in murine models. Blood. 2015;125(21):3326-3334.
25. Feys HB, Roodt J, Vandeputte N, et al. Thrombotic thrombocytopenic purpura directly linked with ADAMTS13 inhibition in the baboon (Papio ursinus). Blood. 2010;116(12):2005-2010.
26. Furlan M, Lammle B. Aetiology and patho- genesis of thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome: the role of von Willebrand factor-cleaving protease. Best Pract Res Clin Haematol. 2001;14(2):437-454.
27. Martinod K, Wagner DD. Thrombosis: tan- gled up in NETs. Blood. 2014;123(18):2768- 2776.
28. Ganz T, Selsted ME, Szklarek D, et al. Defensins. Natural peptide antibiotics of human neutrophils. J Clin Invest. 1985;76 (4):1427-1435.
29. Fuchs TA, Kremer Hovinga JA, Schatzberg D, Wagner DD, Lammle B. Circulating DNA and myeloperoxidase indicate disease activ- ity in patients with thrombotic microan- giopathies. Blood. 2012;120(6):1157-1164.
30. Cao W, Pham HP, Williams LA, et al. Human neutrophil peptides and complement factor Bb in pathogenesis of acquired thrombotic thrombocytopenic purpura. Haematologica. 2016;101(11):1319-1326. .
31. Pillai VG, Bao J, Zander CB, et al. Human neutrophil peptides inhibit cleavage of von Willebrand factor by ADAMTS13: a poten-
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