Endothelial VWF is critical for the pathogenesis of vaso-occlusive episode in a mouse model of sickle cell disease.
Endothelial VWF is critical for the pathogenesis of vaso-occlusive episode in a mouse model of sickle cell disease.
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DOI：
10.1073/pnas.2207592119
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发表时间：
2022-08-23
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
目前镰状细胞病（SCD）的主要治疗方法，如羟基脲、L-谷氨酰胺和crizanlizumab，可降低血管闭塞发作（VOE）的频率。然而，相当数量的SCD患者仍然会发展VOE。例如，尽管发生率显著降低，但在预防性使用高剂量crizanlizumab治疗的SCD患者中仍有64%发生VOE，crizanlizumab是美国食品和药物管理局新批准的一种P-选择素靶向抗体治疗。一旦发生VOE，治疗仅限于支持性治疗。因此，需要更好地了解VOE发病机制和开发新的治疗方法，以有效地管理VOE。我们的研究表明，促进血管性血友病因子切割ADAMTS 13可能是一种有效的治疗，以减轻VOE相关的器官损害。血管闭塞发作（VOE）是镰状细胞病（SCD）常见且严重的并发症。其发病机制尚不完全清楚。血管性血友病因子（vonWillebrand factor，VWF），一种由内皮细胞和血小板合成和分泌的多聚体血浆止血蛋白，在VOE期间增加。然而，VWF是否以及如何参与VOE的发病机制尚不完全清楚。在这项研究中，我们发现在SCD的人源化小鼠模型中，肿瘤坏死因子（TNF）诱导的VOE期间VWF水平增加。在SCD小鼠中，内皮VWF的缺失减少了TNF诱导的VOE引起的溶血、血管闭塞和器官损伤。此外，给予ADAMTS 13，VWF裂解血浆蛋白酶，降低血浆VWF水平，减少炎症和血管闭塞，并减轻VOE期间的器官损伤。这些数据表明，通过ADAMTS 13促进VWF裂解可能是减少VOE期间溶血、炎症和血管闭塞的有效治疗。
Current main treatments for sickle cell disease (SCD), such as hydroxyurea, L-glutamine, and crizanlizumab, reduce the frequency of vaso-occlusive episode (VOE). However, a considerable number of individuals with SCD still develop VOE. For example, although the rate was significantly reduced, VOE still occurred in 64% of individuals with SCD treated with prophylactic use of high-dose crizanlizumab, a P-selectin targeting antibody therapy newly approved by the Food and Drug Administration. Once VOE occurs, treatments are limited to supportive therapies. Thus, a better understanding of mechanisms underlying VOE pathogenesis and development of new therapies are needed to effectively manage VOE. Our study indicates that promoting von Willebrand factor cleavage by ADAMTS13 may be an effective treatment for alleviating VOE-associated organ damage. Vaso-occlusive episode (VOE) is a common and critical complication of sickle cell disease (SCD). Its pathogenesis is incompletely understood. von Willebrand factor (VWF), a multimeric plasma hemostatic protein synthesized and secreted by endothelial cells and platelets, is increased during a VOE. However, whether and how VWF contributes to the pathogenesis of VOE is not fully understood. In this study, we found increased VWF levels during tumor necrosis factor (TNF)–induced VOE in a humanized mouse model of SCD. Deletion of endothelial VWF decreased hemolysis, vascular occlusion, and organ damage caused by TNF-induced VOE in SCD mice. Moreover, administering ADAMTS13, the VWF-cleaving plasma protease, reduced plasma VWF levels, decreased inflammation and vaso-occlusion, and alleviated organ damage during VOE. These data suggest that promoting VWF cleavage via ADAMTS13 may be an effective treatment for reducing hemolysis, inflammation, and vaso-occlusion during VOE.
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影响因子：
158.5
作者：
Niihara, Yutaka;Miller, Scott T.;Vichinsky, Elliott P.
通讯作者：
Vichinsky, Elliott P.
DOI：
10.1111/j.1538-7836.2012.04797.x
发表时间：
2012-08
期刊：
Journal of thrombosis and haemostasis : JTH
影响因子：
--
作者：
Kanaji S;Fahs SA;Shi Q;Haberichter SL;Montgomery RR
通讯作者：
Montgomery RR
影响因子：
20.3
作者：
Tsai, HM
通讯作者：
Tsai, HM
影响因子：
20.3
作者：
Sadler B;Christopherson PA;Haller G;Montgomery RR;Di Paola J
通讯作者：
Di Paola J
影响因子：
20.3
作者：
Furlan, M;Robles, R;Lammle, B
通讯作者：
Lammle, B