Abrams Simon T, Du Min, Shaw Rebecca J, Johnson Carla, McGuinness Dagmara, Schofield Jeremy, Yong Jun, Turtle Lance, Nicolson Phillip L R, Moxon Christopher, Wang Guozheng, Toh Cheng-Hock
Department of Clinical Infection, Microbiology and Immunology, University of Liverpool, Liverpool, United Kingdom; Haematology Department, Liverpool University Hospitals National Health Service Foundation Trust, Liverpool, United Kingdom.
Department of Clinical Infection, Microbiology and Immunology, University of Liverpool, Liverpool, United Kingdom.
J Thromb Haemost. 2024 Apr;22(4):1145-1153. doi: 10.1016/j.jtha.2023.12.008. Epub 2023 Dec 15.
Adenoviral vector-based COVID-19 vaccine-induced immune thrombotic thrombocytopenia (VITT) is rare but carries significant risks of mortality and long-term morbidity. The underlying pathophysiology of severe disease is still not fully understood. The objectives were to explore the pathophysiological profile and examine for clinically informative biomarkers in patients with severe VITT.
Twenty-two hospitalized patients with VITT, 9 pre- and 21 post-ChAdOx1 vaccine controls, were recruited across England, United Kingdom. Admission blood samples were analyzed for cytokine profiles, cell death markers (lactate dehydrogenase and circulating histones), neutrophil extracellular traps, and coagulation parameters. Tissue specimens from deceased patients were analyzed.
There were strong immune responses characterized by significant elevations in proinflammatory cytokines and T helper 1 and 2 cell activation in patients with VITT. Markers of systemic endothelial activation and coagulation activation in both circulation and organ sections were also significantly elevated. About 70% (n = 15/22) of patients met the International Society for Thrombosis and Haemostasis criteria for disseminated intravascular coagulation despite negligible changes in the prothrombin time. The increased neutrophil extracellular trap formation, in conjunction with marked lymphopenia, elevated lactate dehydrogenase, and circulating histone levels, indicates systemic immune cell injury or death. Both lymphopenia and circulating histone levels independently predicted 28-day mortality in patients with VITT.
The coupling of systemic cell damage and death with strong immune-inflammatory and coagulant responses are pathophysiologically dominant and clinically relevant in severe VITT.
基于腺病毒载体的新冠疫苗诱导的免疫性血栓性血小板减少症（VITT）虽罕见，但具有显著的死亡风险和长期发病风险。严重疾病的潜在病理生理学仍未完全明确。目的是探讨严重VITT患者的病理生理学特征，并寻找具有临床指导意义的生物标志物。
在英国英格兰招募了22例住院的VITT患者、9例接种ChAdOx1疫苗前的对照者和21例接种ChAdOx1疫苗后的对照者。对入院时采集的血样进行细胞因子谱、细胞死亡标志物（乳酸脱氢酶和循环组蛋白）、中性粒细胞胞外诱捕网及凝血参数分析。对死亡患者的组织标本进行分析。
VITT患者表现出强烈的免疫反应，其特征为促炎细胞因子显著升高以及辅助性T细胞1和2细胞激活。循环和器官切片中的全身内皮细胞激活和凝血激活标志物也显著升高。尽管凝血酶原时间变化可忽略不计，但约70%（n = 15/22）的患者符合国际血栓与止血学会的弥散性血管内凝血标准。中性粒细胞胞外诱捕网形成增加，同时伴有明显的淋巴细胞减少、乳酸脱氢酶升高和循环组蛋白水平升高，提示全身免疫细胞损伤或死亡。淋巴细胞减少和循环组蛋白水平均独立预测了VITT患者的28天死亡率。
在严重VITT中，全身细胞损伤和死亡与强烈的免疫炎症和凝血反应的耦合在病理生理学上占主导地位且具有临床相关性。
