Altered VWF:ADAMTS13 homeostasis is a target for therapeutic intervention in sickle cell disease.
Altered VWF:ADAMTS13 homeostasis is a target for therapeutic intervention in sickle cell disease.
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DOI：
10.1073/pnas.2213079119
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发表时间：
2022-10-04
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
镰状细胞病（SCD）是最常见的遗传性血液疾病，它影响着全世界数百万人。在SCD中，主要事件是红细胞中异常血红蛋白的聚合，导致血管内和血管外的一系列后遗症，包括慢性溶血、促炎状态和内皮生物标志物的上调，导致红细胞和活化的白细胞和血小板的黏附性增加。血管闭塞发作（VOEs）是SCD的临床病理特征。VOE的发病机制很复杂，包括镰状红细胞粘附内皮，导致血管损伤、内膜增殖和血管收缩(1)。这导致血栓形成前和促炎改变，导致额外的红细胞粘附在内皮上，并促进血小板和富含纤维蛋白的微血栓的形成，从而进一步加强微血管闭塞。VOE随后引发组织缺血-再灌注损伤，从而增强内皮功能障碍和氧化应激，引发全身性炎症反应，可发展为急性胸综合征和多器官功能障碍综合征（2,3）。尽管大多数肺水肿可以在家中进行治疗(4)，但肺水肿仍然是SCD儿童和成人住院的最常见原因。只有三种联邦食品和药物管理局批准的治疗方法可以降低SCD中VOE的发生率（羟基脲、克里赞单抗和l -谷氨酰胺）。目前还没有靶向治疗来减轻急性VOE期间的疼痛和终末器官损伤，支持性治疗，如水合和阿片类镇痛，仍然是主要的治疗方法。为了解决在预防VOEs方面的治疗缺口，Shi等人(5)研究了Von Willebrand因子（VWF）在患有VOE的镰状细胞小鼠中的作用，以及在镰状细胞VOE小鼠模型中，一种VWF切割蛋白酶ADAMTS13在减少炎症、血管闭塞和器官损伤方面的作用。第四种药物可能以完全不同的作用机制提供多模式协同治疗，这是一个潜在的关键突破。Shi等(5)采用腹腔注射肿瘤坏死因子（tumor necrosis factor， TNF）诱导HbSS （Townes）小鼠VOE。总结SCD患者的VOE，实验VOE与血浆VWF水平升高以及多个组织的炎症浸润和血管闭塞有关。肝脏和其他器官的血管闭塞显示VWF、血小板和纤维蛋白染色增加。综上所述，这些发现表明血小板- vwf血栓与VOE有关，并为为什么在VOE小鼠中观察到血小板减少提供了生物学上的合理性。为了证实VWF直接参与了VOE的发病机制，Shi等人(5)生成了缺乏内皮VWF的HbSS小鼠，并表明这些小鼠在TNF挑战下炎症浸润和血管闭塞减少。最后，在TNF注射前用重组ADAMTS13预处理HbSS小鼠。adamts13预处理小鼠的血浆VWF水平较低，炎症细胞因子水平较低，肝脏和其他器官中VWF阳性血栓和红细胞血管闭塞减少。重要的是，TNF注射后治疗HbSS小鼠还导致血管闭塞减少，血小板计数和血红蛋白水平改善，通过改善天冬氨酸转氨酶（AST）和丙氨酸转氨酶（ALT）水平，减少voe相关的器官损伤，减少肝脏缺血和炎症变化，减少肾脏损伤……
Sickle cell disease (SCD) is the most common inherited blood disorder, and it affects millions of people worldwide. In SCD, the primary event is polymerization of abnormal hemoglobin in the red blood cells (RBCs), leading to a cascade of intravascular and extravascular sequelae, including chronic hemolysis, a proinflammatory state, and up-regulation of endothelial biomarkers that lead to increased adhesiveness of RBCs and activated white blood cells and platelets. Vaso-occlusive episodes (VOEs) are the pathognomonic clinical feature of SCD. The pathogenesis of VOE is complex and includes sickled erythrocyte adherence to the endothelium, leading to vessel injury, intimal proliferation, and vasoconstriction (1). This leads to prothrombotic and proinflammatory changes that cause additional red cells to adhere to the endothelium and also promotes the formation of platelet and fibrin rich microthrombi, which further potentiates microvascular occlusion. VOE subsequently triggers tissue ischemia–reperfusion injury, which potentiates endothelial dysfunction and oxidative stress, unleashing a systemic inflammatory response that can progress to acute chest syndrome and multiorgan dysfunction syndrome (2, 3). Despite most VOE being managed at home (4), VOE remains the most common cause of hospital admission for children and adults with SCD. Only three federal Food and Drug Administration therapies are approved to decrease the incidence rate of VOE in SCD (hydroxyurea, crizanlizumab, and L-glutamine). There are currently no targeted therapies to reduce pain and end-organ injury during acute VOE, and supportive therapies, such as hydration and opioid analgesia, remain the mainstay of therapy. To address this therapeutic gap in preventing VOEs, Shi et al.(5) examined the role of the Von Willebrand factor (VWF) in sickle cell mice with VOE and the effect of ADAMTS13, a VWF-cleaving protease, on reducing inflammation, vasoocclusion, and organ damage in a mouse model of sickle cell VOE. The possibility of a fourth agent that may provide multimodal synergistic therapy with a completely different mechanism of action is a potentially critical breakthrough. Shi et al.(5) used intraperitoneal injection of tumor necrosis factor (TNF) to induce VOE in HbSS (Townes) mice. Recapitulating VOE in individuals with SCD, the experimental VOE was associated with increased plasma VWF levels as well as inflammatory infiltrates and vascular occlusions in multiple tissues. Vaso-occlusions in the liver and other organs showed increased staining for VWF, platelets, and fibrin. Taken together, these findings suggest that platelet–VWF thrombi are associated with VOE and provide biological plausibility for why thrombocytopenia is observed in mice with VOE. To establish that VWF contributes directly to the pathogenesis of VOE, Shi et al.(5) generated HbSS mice lacking endothelial VWF and showed that these mice have reduced inflammatory infiltrates and vaso-occlusions in response to TNF challenge. Finally, the group pretreated HbSS mice with recombinant ADAMTS13 before TNF injection. ADAMTS13-pretreated mice had lower levels of plasma VWF, lower levels of inflammatory cytokines, and reduced VWF-positive thrombi and RBC vaso-occlusions in the liver and other organs. Importantly, treating HbSS mice after TNF injection also led to less vaso-occlusion, improvement in platelet count and hemoglobin levels, and reduced VOE-associated organ damage with improvement in Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) levels, reduced ischemic and inflammatory changes in the liver, and reduced injury to the kidneys …
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影响因子：
1.9
作者：
Aref, Salah;Goda, Hosam
通讯作者：
Goda, Hosam
DOI：
10.1111/jth.15409
发表时间：
2021-08
期刊：
Journal of thrombosis and haemostasis : JTH
影响因子：
--
作者：
Ward SE;Fogarty H;Karampini E;Lavin M;Schneppenheim S;Dittmer R;Morrin H;Glavey S;Ni Cheallaigh C;Bergin C;Martin-Loeches I;Mallon PW;Curley GF;Baker RI;Budde U;O'Sullivan JM;O'Donnell JS;Irish COVID-19 Vasculopathy Study (iCVS) investigators
通讯作者：
Irish COVID-19 Vasculopathy Study (iCVS) investigators
影响因子：
6.7
作者：
Schwameis M;Schörgenhofer C;Assinger A;Steiner MM;Jilma B
通讯作者：
Jilma B
影响因子：
2.4
作者：
Hebbel, Robert P.
通讯作者：
Hebbel, Robert P.
影响因子：
39.2
作者：
Smith, Wally R.;Penberthy, Lynne T.;Roseff, Susan D.
通讯作者：
Roseff, Susan D.