新英格兰 接种阿斯利康新冠疫苗ChAdOx1 nCov-19可导致罕见免疫性血栓性血小板减少症

背景:


新冠疫情流行至今尚未结束,目前,各国也已经研发出多款新冠疫苗以期早日遏制疫情。各款疫苗的有效率和安全性往往是民众最为关心的话题。2021年6月3日,《新英格兰医学杂志》公布了阿斯利康新冠疫苗ChAdOx1 nCov-19引发的一种副作用——血栓性血小板减少症。


截至2021年4月7日,德国已有大约四分之一的疫苗接种者接种了ChAdOx1 nCov-19疫苗。而从2021年2月下旬开始,在这些接种者中观察到了几例异常血栓事件与血小板减少症相关。


方法:


研究者评估了德国和奥地利11例接种ChAdOx1 nCov-19后发生血栓或血小板减少患者的临床和实验室特征。使用标准酶联免疫吸附试验检测了血小板因子4(PF4)-肝素抗体和改良的PF4增强血小板活化试验在各种不同反应条件下的血小板活化抗体。这项试验包括来自血液样本用于疫苗相关血栓性事件调查的患者的样本,其中28例在筛选PF4-肝素免疫分析中呈阳性。


结果:


11位患者中,有9位是女性,中位年龄为36岁(范围为22至49岁)。接种疫苗后5至16天,除1例出现致命性颅内出血外,其余患者均发生一次或多次血栓。在出现一次或多次血栓事件的患者中,9例发生脑静脉血栓,3例发生内脏静脉血栓,3例出现肺栓塞,4例出现其他血栓形成;在这些患者中,有6人死亡。5例患者出现弥散性血管内凝血。所有患者在症状出现前均未接受肝素治疗。在不依赖肝素的PF4存在下,所有28例抗PF4-肝素抗体检测呈阳性的患者,在血小板活化试验中均呈阳性。高水平的肝素,阻断Fc受体单克隆抗体和免疫球蛋白(每毫升10 mg)可抑制血小板活化。另外对2例患者中使用PF4或PF4-肝素亲和纯化抗体进行的其他研究证实了PF4依赖性血小板活化。

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上图为具有可用临床信息的11名患者的临床和实验室特征总结


结论:


接种ChAdOx1 nCov-19疫苗可导致罕见的由抗PF4的血小板活化抗体介导的免疫性血栓性血小板减少症,这在临床上类似于自身免疫性肝素诱导的血小板减少症。


原文摘要:


Background: 


Several cases of unusual thrombotic events and thrombocytopenia have developed after vaccination with the recombinant adenoviral vector encoding the spike protein antigen of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (ChAdOx1 nCov-19, AstraZeneca). More data were needed on the pathogenesis of this unusual clotting disorder.


Methods: 


We assessed the clinical and laboratory features of 11 patients in Germany and Austria in whom thrombosis or thrombocytopenia had developed after vaccination with ChAdOx1 nCov-19. We used a standard enzyme-linked immunosorbent assay to detect platelet factor 4 (PF4)-heparin antibodies and a modified (PF4-enhanced) platelet-activation test to detect platelet-activating antibodies under various reaction conditions. Included in this testing were samples from patients who had blood samples referred for investigation of vaccine-associated thrombotic events, with 28 testing positive on a screening PF4-heparin immunoassay.


Results: 


Of the 11 original patients, 9 were women, with a median age of 36 years (range, 22 to 49). Beginning 5 to 16 days after vaccination, the patients presented with one or more thrombotic events, with the exception of 1 patient, who presented with fatal intracranial hemorrhage. Of the patients with one or more thrombotic events, 9 had cerebral venous thrombosis, 3 had splanchnic-vein thrombosis, 3 had pulmonary embolism, and 4 had other thromboses; of these patients, 6 died. Five patients had disseminated intravascular coagulation. None of the patients had received heparin before symptom onset. All 28 patients who tested positive for antibodies against PF4-heparin tested positive on the platelet-activation assay in the presence of PF4 independent of heparin. Platelet activation was inhibited by high levels of heparin, Fc receptor-blocking monoclonal antibody, and immune globulin (10 mg per milliliter). Additional studies with PF4 or PF4-heparin affinity purified antibodies in 2 patients confirmed PF4-dependent platelet activation.


Conclusions: 


Vaccination with ChAdOx1 nCov-19 can result in the rare development of immune thrombotic thrombocytopenia mediated by platelet-activating antibodies against PF4, which clinically mimics autoimmune heparin-induced thrombocytopenia. (Funded by the German Research Foundation.).


参考文献:


Greinacher A, Thiele T, Warkentin TE, Weisser K, Kyrle PA, Eichinger S. Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination. N Engl J Med. 2021 Jun 3;384(22):2092-2101. doi: 10.1056/NEJMoa2104840. Epub 2021 Apr 9. PMID: 33835769; PMCID: PMC8095372.





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