实验室确诊的疫苗诱导免疫性血栓性血小板减少症：德国接种ChAdOx-1 nCoV-19疫苗后报告病例的回顾性分析
Laboratory confirmed vaccine-induced immune thrombotic thrombocytopenia: Retrospective analysis of reported cases after vaccination with ChAdOx-1 nCoV-19 in Germany.
作者信息
Thiele Thomas, Weisser Karin, Schönborn Linda, Funk Markus B, Weber Gabriele, Greinacher Andreas, Keller-Stanislawski Brigitte
机构信息
Institut für Immunologie und Transfusionsmedizin, Universitätsmedizin Greifswald.
Paul-Ehrlich-Institut (Federal Institute for Vaccines and Biomedicines), Division Safety of Medicinal Products and Medical Devices, Langen, Germany.
出版信息
Lancet Reg Health Eur. 2022 Jan;12:100270. doi: 10.1016/j.lanepe.2021.100270. Epub 2021 Dec 6.
BACKGROUND
Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a severe adverse event of SARS-CoV-2 vaccination. We describe the characteristics of patients reported in Germany based on the Brighton Collaboration (BC) case definition criteria for Thrombosis and Thrombocytopenia Syndrome (TTS) and focus on patients with complete anti-platelet factor 4 (PF4)-antibody laboratory work up.
METHODS
The adverse drug reaction database of the Paul-Ehrlich Institute was queried for TTS cases following ChAdOx1 nCoV-19 vaccination from February 1, until May 21, 2021. Cases with reports from the Greifswald laboratory were analysed in detail.
FINDINGS
PF4 antibody tests were available for 69 suspected TTS cases reported to the Paul-Ehrlich Institute, of whom 52 patients fulfilled the BC case definition; 37 (71%) women, 15 (29%) men, median age 46·0 years (interquartile range 31·0-60·3 years). Cerebral venous sinus thrombosis was confirmed in 37 (71%), (additional) multiple thromboses in 19 (37%) patients. Twelve patients died. Non-survivors showed lower platelet counts compared to survivors (median nadir 15,000/µL vs 49,000/µL; p<0·0001). Combined anti-PF4/heparin IgG ELISA and PF4-dependent platelet activation testing yielded sensitivity of 96% (95% confidence interval 87-100%) and specificity of 77% (50-93%) for TTS. Four patients with thrombocytopenia but without thrombosis presented with severe headache or cerebral bleeding, explaining the lower specificity.
INTERPRETATION
VITT has high mortality and can present with isolated thrombocytopenia, severe headache, and bleeding. Demonstration of platelet activating anti-PF4 IgG has high sensitivity for TTS and captures a wider spectrum of clinically relevant VITT than the current BC case definition.
FUNDING
Deutsche Forschungsgemeinschaft: 374031971-TRR240; Domagk-Programm Universitätsmedizin Greifswald.
背景
疫苗诱导的免疫性血栓性血小板减少症（VITT）是新型冠状病毒肺炎疫苗接种的一种严重不良事件。我们根据布莱顿协作组织（BC）关于血栓形成和血小板减少综合征（TTS）的病例定义标准，描述德国报告的患者特征，并重点关注抗血小板因子4（PF4）抗体实验室检查完整的患者。
方法
查询保罗·埃利希研究所的药物不良反应数据库，以获取2021年2月1日至5月21日接种ChAdOx1 nCoV-19疫苗后发生TTS的病例。对来自格赖夫斯瓦尔德实验室报告的病例进行详细分析。
结果
保罗·埃利希研究所报告的69例疑似TTS病例进行了PF4抗体检测，其中52例患者符合BC病例定义；37例（71%）为女性，15例（29%）为男性，中位年龄46.0岁（四分位间距31.0 - 60.3岁）。37例（71%）确诊为脑静脉窦血栓形成，19例（37%）患者有（额外的）多处血栓形成。12例患者死亡。与幸存者相比，非幸存者的血小板计数更低（最低值中位数15,000/µL对49,000/µL；p<0.0001）。联合抗PF4/肝素IgG酶联免疫吸附测定和PF4依赖性血小板活化检测对TTS的敏感性为96%（95%置信区间87 - 100%），特异性为77%（50 - 93%）。4例血小板减少但无血栓形成的患者出现严重头痛或脑出血，这解释了特异性较低的原因。
解读
VITT死亡率高，可表现为孤立性血小板减少、严重头痛和出血。血小板活化抗PF4 IgG检测对TTS具有高敏感性，且比当前的BC病例定义涵盖了更广泛的临床相关VITT范围。
资助
德国研究基金会：374031971 - TRR240；格赖夫斯瓦尔德大学医学多马克项目。
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