ADAMTS13 regulation of VWF multimer distribution in severe COVID-19.
ADAMTS13 regulation of VWF multimer distribution in severe COVID-19.
复制标题
DOI：
10.1111/jth.15409
复制
发表时间：
2021-08
期刊：
影响因子：
--
通讯作者：
Irish COVID-19 Vasculopathy Study (iCVS) investigators
中科院分区：
文献类型：
--
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
与暴发性内皮细胞活化一致，在COVID-19患者中报告了血浆血管性血友病因子（VWF）抗原水平升高。VWF的多聚体大小和功能通常通过具有血栓形成蛋白基序1型基序的去整合素和金属蛋白酶，成员13（ADAMTS-13）介导的蛋白水解来调节。本研究探讨了ADAMTS-13对VWF多聚体分布的调节可能在严重急性呼吸综合征-冠状病毒-2（SARS-CoV-2）感染中受损，导致观察到的微血管血栓形成的假设。从都柏林的博蒙医院重症监护室（ICU）招募了23例COVID-19患者。评估了血浆VWF抗原、多聚体分布、ADAMTS-13活性及其已知抑制剂。我们观察到与对照组相比，重度COVID-19患者的VWF胶原结合活性显著增加（中位数为509.1 vs 94.3 IU/dl）。相反，血浆ADAMTS-13活性显著降低（中位数68.2 IU/dl）。与VWF：ADAMTS-13比值增加一致，VWF多聚体分布异常在COVID-19患者中很常见，高分子量VWF多聚体减少。末端唾液酸化调节VWF对ADAMTS-13和其他蛋白酶的蛋白水解的敏感性。我们观察到，在严重的COVID-19中，N-和O-连接的唾液酸化都发生了改变。此外，ADAMTS-13抑制剂白细胞介素-6、血小板反应蛋白-1和血小板因子4的血浆水平显著升高。这些发现支持了这样的假设，即SARS-CoV-2与血浆VWF水平的定量和定性增加以及ADAMTS-13功能的多因素下调相关。需要进一步研究以确定纠正ADAMTS-13-VWF多聚体功能障碍的治疗干预是否可用于COVID微血管血栓形成和血管病。
Consistent with fulminant endothelial cell activation, elevated plasma von Willebrand factor (VWF) antigen levels have been reported in patients with COVID‐19. The multimeric size and function of VWF are normally regulated through A Disintegrin And Metalloprotease with ThrombSpondin Motif type 1 motif, member 13 (ADAMTS‐13)‐‐mediated proteolysis. This study investigated the hypothesis that ADAMTS‐13 regulation of VWF multimer distribution may be impaired in severe acute respiratory syndrome‐coronavirus‐2 (SARS‐CoV‐2) infection contributing to the observed microvascular thrombosis. Patients with COVID‐19 (n = 23) were recruited from the Beaumont Hospital Intensive Care Unit (ICU) in Dublin. Plasma VWF antigen, multimer distribution, ADAMTS‐13 activity, and known inhibitors thereof were assessed. We observed markedly increased VWF collagen‐binding activity in patients with severe COVID‐19 compared to controls (median 509.1 versus 94.3 IU/dl). Conversely, plasma ADAMTS‐13 activity was significantly reduced (median 68.2 IU/dl). In keeping with an increase in VWF:ADAMTS‐13 ratio, abnormalities in VWF multimer distribution were common in patients with COVID‐19, with reductions in high molecular weight VWF multimers. Terminal sialylation regulates VWF susceptibility to proteolysis by ADAMTS‐13 and other proteases. We observed that both N‐ and O‐linked sialylation were altered in severe COVID‐19. Furthermore, plasma levels of the ADAMTS‐13 inhibitors interleukin‐6, thrombospondin‐1, and platelet factor 4 were significantly elevated. These findings support the hypothesis that SARS‐CoV‐2 is associated with profound quantitative and qualitative increases in plasma VWF levels, and a multifactorial down‐regulation in ADAMTS‐13 function. Further studies will be required to determine whether therapeutic interventions to correct ADAMTS‐13‐VWF multimer dysfunction may be useful in COVID‐microvascular thrombosis and angiopathy.
登录
查看更多内容
影响因子：
7.5
作者：
Turecek PL;Peck RC;Rangarajan S;Reilly-Stitt C;Laffan MA;Kazmi R;James I;Dushianthan A;Schrenk G;Gritsch H;Ewenstein BM;Mellgard B;Erdlenbruch W;Jain N;Binder NB;Mumford AD
通讯作者：
Mumford AD
影响因子：
20.3
作者：
Aguila, Sonia;Lavin, Michelle;O'Donnell, James S.
通讯作者：
O'Donnell, James S.
影响因子：
158.5
作者：
Ackermann, Maximilian;Verleden, Stijn E.;Jonigk, Danny
通讯作者：
Jonigk, Danny
DOI：
10.1161/atvbaha.120.315338
发表时间：
2021-01
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Bouck EG;Denorme F;Holle LA;Middelton EA;Blair AM;de Laat B;Schiffman JD;Yost CC;Rondina MT;Wolberg AS;Campbell RA
通讯作者：
Campbell RA
影响因子：
6.5
作者：
Nazy, Ishac;Elliott, Taylor D.;Arnold, Donald M.
通讯作者：
Arnold, Donald M.