Insights in ChAdOx1 nCoV-19 vaccine-induced immune thrombotic thrombocytopenia.
Insights in ChAdOx1 nCoV-19 vaccine-induced immune thrombotic thrombocytopenia.
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ChAdOx 1 nCoV-19疫苗诱导的免疫血栓性血小板减少症的见解。
DOI：
10.1182/blood.2021013231
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发表时间：
2021-12-02
期刊：
影响因子：
20.3
通讯作者：
Renné T
中科院分区：
文献类型：
--
作者：
Greinacher A;Selleng K;Palankar R;Wesche J;Handtke S;Wolff M;Aurich K;Lalk M;Methling K;Völker U;Hentschker C;Michalik S;Steil L;Reder A;Schönborn L;Beer M;Franzke K;Büttner A;Fehse B;Stavrou EX;Rangaswamy C;Mailer RK;Englert H;Frye M;Thiele T;Kochanek S;Krutzke L;Siegerist F;Endlich N;Warkentin TE;Renné T
Greinacher等人详细描述了疫苗诱导的免疫性血栓性血小板减少症(VITT)的潜在发病机制。他们认为，维生素T的发病机制涉及一个两步机制，首先是血小板因子4与ChadOX1 NCoV-19腺病毒疫苗的成分结合，然后是类似于自身免疫性肝素诱导的血小板减少症的血栓前抗体反应。这项工作有助于解释临床观察，并建议对未来的疫苗生产进行修改，以降低维生素T的风险。ChAdOx1 nCoV-19疫苗含有人TRex HEK293细胞衍生蛋白和EDTA。疫苗成分和PF4在血小板表面形成复合体，Vitt患者抗体与其结合。SARS-CoV-2疫苗ChAdOx1 nCoV-19(阿斯利康)引起一种血栓栓塞性并发症，称为疫苗诱导的免疫性血栓性血小板减少症(VITT)。利用生物物理技术、小鼠模型和对VITT患者样本的分析，我们确定了这种疫苗引起的不良反应的决定因素。超分辨率显微镜观察到疫苗成分与血小板因子4(PF4)在血小板表面形成抗原复合体，从VITT患者获得的抗PF4抗体与其结合。PF4/疫苗复合体的形成是电荷驱动的，DNA的加入促进了PF4/疫苗复合物的形成。蛋白质组学在含有乙二胺四乙酸(EDTA)的疫苗中发现了大量由病毒产生的T-Rex HEK293蛋白。注射疫苗增加了小鼠的血管渗漏，导致已知的刺激免疫反应的疫苗成分系统性传播。总而言之，PF4/疫苗复合体的形成和疫苗刺激的促炎环境触发了显著的B细胞反应，导致VITT患者形成高亲和力的抗PF4抗体。由此产生的高效价抗PF4抗体在存在PF4或DNA和聚磷酸多阴离子的情况下有效地激活了血小板。抗PF4-Vitt患者抗体还刺激中性粒细胞以血小板PF4依赖的方式释放中性粒细胞外陷阱(Net)。VITT患者血清中促凝剂NETs的生物标志物水平升高，免疫组织化学方法显示在VITT患者的脑静脉血栓中可见丰富的Net。综上所述，疫苗诱导的PF4/腺病毒聚集和促炎反应刺激病理性抗PF4抗体的产生，从而推动维生素T中的血栓形成。这些数据支持维生素T的两步机制，类似于(自身免疫性)肝素诱导的血小板减少的发病机制。
Greinacher et al report a detailed characterization of a potential mechanism underlying the pathogenesis of vaccine-induced immune thrombotic thrombocytopenia (VITT). They propose that the pathogenesis of VITT involves a 2-step mechanism, initiated by binding of platelet factor 4 to components of the ChadOX1 nCov-19 adenoviral vaccine followed by a prothrombotic antibody response similar to autoimmune heparin-induced thrombocytopenia. This work helps explain the clinical observations and also suggests modifications to future vaccine production to reduce the risk of VITT. ChAdOx1 nCoV-19 vaccine contains human TRex HEK293 cell-derived proteins and EDTA. Vaccine components and PF4 form complexes on platelet surfaces to which VITT patient antibodies bind. SARS-CoV-2 vaccine ChAdOx1 nCoV-19 (AstraZeneca) causes a thromboembolic complication termed vaccine-induced immune thrombotic thrombocytopenia (VITT). Using biophysical techniques, mouse models, and analysis of VITT patient samples, we identified determinants of this vaccine-induced adverse reaction. Super-resolution microscopy visualized vaccine components forming antigenic complexes with platelet factor 4 (PF4) on platelet surfaces to which anti-PF4 antibodies obtained from VITT patients bound. PF4/vaccine complex formation was charge-driven and increased by addition of DNA. Proteomics identified substantial amounts of virus production-derived T-REx HEK293 proteins in the ethylenediaminetetraacetic acid (EDTA)-containing vaccine. Injected vaccine increased vascular leakage in mice, leading to systemic dissemination of vaccine components known to stimulate immune responses. Together, PF4/vaccine complex formation and the vaccine-stimulated proinflammatory milieu trigger a pronounced B-cell response that results in the formation of high-avidity anti-PF4 antibodies in VITT patients. The resulting high-titer anti-PF4 antibodies potently activated platelets in the presence of PF4 or DNA and polyphosphate polyanions. Anti-PF4 VITT patient antibodies also stimulated neutrophils to release neutrophil extracellular traps (NETs) in a platelet PF4-dependent manner. Biomarkers of procoagulant NETs were elevated in VITT patient serum, and NETs were visualized in abundance by immunohistochemistry in cerebral vein thrombi obtained from VITT patients. Together, vaccine-induced PF4/adenovirus aggregates and proinflammatory reactions stimulate pathologic anti-PF4 antibody production that drives thrombosis in VITT. The data support a 2-step mechanism underlying VITT that resembles the pathogenesis of (autoimmune) heparin-induced thrombocytopenia.
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参与肝素诱导的血小板减少症的免疫复合物的原子描述。
影响因子：
16.6
作者：
Cai Z;Yarovoi SV;Zhu Z;Rauova L;Hayes V;Lebedeva T;Liu Q;Poncz M;Arepally G;Cines DB;Greene MI
通讯作者：
Greene MI
DOI：
10.3390/v12121351
发表时间：
2020-11-26
期刊：
Viruses
影响因子：
--
作者：
Chéneau C;Kremer EJ
通讯作者：
Kremer EJ
DOI：
10.1056/nejmoa2104840
发表时间：
2021-06-03
期刊：
The New England journal of medicine
影响因子：
--
作者：
Greinacher A;Thiele T;Warkentin TE;Weisser K;Kyrle PA;Eichinger S
通讯作者：
Eichinger S
影响因子：
7.3
作者：
Kasonta R;Mauritz J;Spohr C;Sauter-Louis C;Duchow K;Cussler K;Holsteg M;Bastian M
通讯作者：
Bastian M
影响因子：
7.3
作者：
Garis M;Garrett-Sinha LA
通讯作者：
Garrett-Sinha LA