Thromboembolic complication is common in severe coronavirus disease 2019 (COVID-19), leading to an investigation into the presence of prothrombotic antibodies akin to those found in heparin-induced thrombocytopenia (HIT). In a study of samples from 130 hospitalized patients, collected 3.6 days after COVID-19 diagnosis, 80% had immunoglobulin G (IgG) antibodies recognizing complexes of heparin and platelet factor 4 (PF4; PF4/H), and 41% had antibodies inducing PF4-dependent P-selectin expression in CpG-treated normal platelets. Unlike HIT, both PF4/H-reactive and platelet-activating antibodies were found in patients with COVID-19 regardless of recent heparin exposure. Notably, PF4/H-reactive IgG antibodies correlated with those targeting the receptor-binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 spike protein. Moreover, introducing exogenous RBD to or removing RBD-reactive IgG from COVID-19 plasma or IgG purified from COVID-19 plasma significantly reduced their ability to activate platelets. RBD-specific antibodies capable of platelet activation were cloned from peripheral blood B cells of patients with COVID-19. These antibodies possessed sequence motifs in the heavy-chain complementarity-determining region 3 (HCDR3), resembling those identified in pathogenic HIT antibodies. Furthermore, IgG+ B cells having these HCDR3 signatures were markedly expanded in patients with severe COVID-19. Importantly, platelet-activating antibodies present in patients with COVID-19 were associated with a specific elevation of platelet α-granule proteins in the plasma and showed a positive correlation with markers for inflammation and tissue damage, suggesting a functionality of these antibodies in patients. The demonstration of functional and structural similarities between certain RBD-specific antibodies in patients with COVID-19 and pathogenic antibodies typical of HIT suggests a novel mechanism by which RBD-specific antibodies might contribute to thrombosis in COVID-19.

中文翻译：

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在重症 COVID-19 中靶向刺突蛋白受体结合域的血栓前抗体


血栓栓塞并发症在 2019 年重症冠状病毒病 （COVID-19） 中很常见，因此需要调查是否存在类似于肝素诱导的血小板减少症 （HIT） 中发现的促血栓形成抗体。在一项对 130 名住院患者样本的研究中，在 COVID-19 诊断后 3.6 天收集，80% 的患者具有识别肝素和血小板因子 4 复合物的免疫球蛋白 G （IgG） 抗体 （PF4;PF4/H），41% 的抗体诱导 CpG 处理的正常血小板中 PF4 依赖性 P-选择素表达。与 HIT 不同，无论近期肝素暴露情况如何，在 COVID-19 患者中均发现 PF4/H 反应性和血小板活化抗体。值得注意的是，PF4/H 反应性 IgG 抗体与靶向严重急性呼吸系统综合症冠状病毒 2 刺突蛋白受体结合域 （RBD） 的抗体相关。此外，将外源性 RBD 引入 COVID-19 血浆或从 COVID-19 血浆中纯化的 IgG 中去除 RBD 反应性 IgG 会显著降低它们激活血小板的能力。能够使血小板活化的 RBD 特异性抗体是从 COVID-19 患者的外周血 B 细胞中克隆的。这些抗体在重链互补决定区 3 （HCDR3） 中具有序列基序，类似于在致病性 HIT 抗体中鉴定的基序。此外，具有这些 HCDR3 特征的 IgG+ B 细胞在重症 COVID-19 患者中显着扩增。重要的是，COVID-19 患者中存在的血小板活化抗体与血浆中血小板α颗粒蛋白的特异性升高有关，并且与炎症和组织损伤的标志物呈正相关，表明这些抗体在患者中具有功能性。 COVID-19 患者的某些 RBD 特异性抗体与 HIT 的典型致病性抗体之间的功能和结构相似性证明表明 RBD 特异性抗体可能有助于 COVID-19 血栓形成的新机制。