Background: Immunohematologic complications, including thrombosis and thrombocytopenia syndrome (TTS) (1), immune thrombocytopenia (2), and autoimmune hemolytic anemia (3), have been reported after vaccination against COVID-19. Thrombocytopenia after COVID-19 adenoviral vector vaccination is of particular concern due to the potential for TTS, but other causes of vaccine-related thrombocytopenia must be investigated and characterized.

Objective: To illustrate an alternative cause of thrombocytopenia, transient glycoprotein-specific platelet autoantibodies, after receipt of a COVID-19 adenoviral vector vaccine (Ad26.COV2.S; Johnson & Johnson).

Case Report: We evaluated a 71-year-old woman with a history of polymyalgia rheumatica who presented with acute thrombocytopenia after receipt of the Ad26.COV2.S vaccine. The patient had been diagnosed with polymyalgia rheumatica 6 years prior, which remitted on completion of a 3-month course of low-dose prednisone and did not recur. Before vaccination, the patient was in good health; 3 weeks prior, a routine examination showed an unremarkable complete blood count and a platelet count of 429 × 10⁹ cells/L. However, 35 days after vaccination, she developed headaches in the left temporal region, prompting evaluation by her rheumatologist for possible giant cell arteritis given her history of polymyalgia rheumatica. She did not report recurrence of polymyalgia rheumatica symptoms, and giant cell arteritis was believed to be unlikely after laboratory evaluation showed an erythrocyte sedimentation rate of 8 mm/h (reference, 0 to 20 mm/h) and a C-reactive protein level of 1.0 mg/L (reference, <8.0 mg/L). However, this same evaluation did show isolated thrombocytopenia (platelet count, 115 × 10⁹ cells/L) with no other complete blood count abnormalities. The patient did not have a preexisting immune thrombocytopenia diagnosis but had experienced brief mild thrombocytopenia (platelet count, 55 to 110 × 10⁹ cells/L) in the setting of an acute right ear infection in the previous year. Given ongoing headaches and recent receipt of an adenoviral vector SARS-CoV-2 vaccine, the patient was further evaluated using magnetic resonance angiography of the brain and a heparin–platelet factor 4 antibody enzyme-linked immunosorbent assay, both of which had unremarkable findings (the assay optical density was 0.057; reference, <0.400). The patient's headaches were ultimately attributed to referred dental pain due to occlusal trauma from a temporary dental bridge, and they resolved after dental intervention.

The patient's platelet count further declined to 96 × 10⁹ cells/L on postvaccination day 38 and then to 59 × 10⁹ cells/L on postvaccination day 42. At this time, platelet autoantibodies were assessed using a direct, solid-phase, enzyme-linked immunosorbent assay measuring antibodies against glycoproteins IIb/IIIa, Ib/IX, and Ia/IIa eluted from the platelet surface (Versiti). Testing was done following expert recommendations (4), and the results were positive for platelet autoantibodies directed against all 3 glycoproteins at optical densities of 0.119 for anti–glycoprotein IIb/IIIa (threshold, ≥0.090), 0.180 for anti–glycoprotein Ib/IX (threshold, ≥0.094), and 0.267 for anti–glycoprotein Ia/IIa (threshold, ≥0.108). The optical density positivity thresholds for each glycoprotein in this assay are set to twice the normal calibrator values (which are averaged from antibody-negative plasma samples from healthy donors).

The patient's platelet count was monitored closely and showed stability and rapid recovery without intervention as follows: at 43 days, 56 × 10⁹ cells/L; at 44 days, 67 × 10⁹ cells/L; at 45 days, 76 × 10⁹ cells/L; at 48 days, 143 × 10⁹ cells/L; and at 51 days, 248 × 10⁹ cells/L. Platelet autoantibody testing was repeated 3 weeks after platelet count normalization; results for all 3 platelet glycoproteins were negative.

Discussion: Platelet autoantibody testing is not routinely recommended in patients with suspected immune thrombocytopenia because of its modest sensitivity (about 50%) (5). However, when glycoprotein-specific antibody testing is done in adherence with expert guidelines, specificity is 90% to 95% (4, 5). Although many vaccines are associated with thrombocytopenia, the occurrence of potentially fatal TTS may be uniquely associated with adenoviral vector vaccines against SARS-CoV-2. Therefore, characterizing the natural history of alternative causes of new-onset acute thrombocytopenia in recipients of these vaccines is of paramount importance. In this case, the patient had an initial presentation that was concerning for possible TTS, but on further evaluation, she was found to have transient immunologic thrombocytopenia with detected (and similarly transient) direct glycoprotein-specific platelet autoantibodies, suggesting that vaccination with Ad26.COV2.S may provoke transient production of antibodies targeted against, or capable of cross-reactivity with, platelet glycoproteins in certain individuals. If antiviral spike protein antibodies cross-reactive with platelet glycoproteins resulted in this clinical presentation, thrombocytopenia due to this mechanism could occur with other SARS-CoV-2 vaccines. The potential development of platelet autoantibodies or antiviral antibodies capable of cross-reactivity with platelet glycoproteins after vaccination against SARS-CoV-2 is a phenomenon worthy of further study.

Hanny Al-Samkari, MD

Rebecca Karp Leaf, MD

Katayoon Goodarzi, MD

Massachusetts General Hospital and Harvard Medical School

Boston, Massachusetts

References

• 1. Schultz NH ,  Sørvoll IH ,  Michelsen AE , et al. Thrombosis and thrombocytopenia after ChAdOx1 nCoV-19 vaccination. N Engl J Med. 2021;384:2124-30. [PMID: 33835768] doi:10.1056/NEJMoa2104882 CrossrefMedlineGoogle Scholar
• 2. Lee EJ ,  Cines DB ,  Gernsheimer T , et al. Thrombocytopenia following Pfizer and Moderna SARS-CoV-2 vaccination. Am J Hematol. 2021;96:534-7. [PMID: 33606296] doi:10.1002/ajh.26132 CrossrefMedlineGoogle Scholar
• 3. Brito S ,  Ferreira N ,  Mateus S , et al. A case of autoimmune hemolytic anemia following COVID-19 messenger ribonucleic acid vaccination. Cureus. 2021;13:e15035. [PMID: 34150386] doi:10.7759/cureus.15035 CrossrefMedlineGoogle Scholar
• 4. Arnold DM ,  Santoso S ,  Greinacher A ; Platelet Immunology Scientific Subcommittee of the ISTH. Recommendations for the implementation of platelet autoantibody testing in clinical trials of immune thrombocytopenia. J Thromb Haemost. 2012;10:695-7. [PMID: 22332994] doi:10.1111/j.1538-7836.2012.04664.x CrossrefMedlineGoogle Scholar
• 5. Vrbensky JR ,  Moore JE ,  Arnold DM , et al. The sensitivity and specificity of platelet autoantibody testing in immune thrombocytopenia: a systematic review and meta-analysis of a diagnostic test. J Thromb Haemost. 2019;17:787-94. [PMID: 30801909] doi:10.1111/jth.14419 CrossrefMedlineGoogle Scholar

中文翻译：

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Ad26.COV2.S 疫苗接种后出现糖蛋白特异性血小板自身抗体的一过性血小板减少症：病例报告

背景：免疫血液学并发症，包括血栓形成和血小板减少症 (TTS) (1)、免疫性血小板减少症 (2) 和自身免疫性溶血性贫血 (3)，在接种 COVID-19 疫苗后已有报道。由于可能发生 TTS，COVID-19 腺病毒载体疫苗接种后的血小板减少症尤其令人担忧，但必须调查和表征疫苗相关血小板减少症的其他原因。

目的：为了说明接受 COVID-19 腺病毒载体疫苗（Ad26.COV2.S；强生公司）后血小板减少症的另一个原因，即暂时性糖蛋白特异性血小板自身抗体。

病例报告：我们评估了一名有风湿性多肌痛病史的 71 岁女性，她在接种 Ad26.COV2.S 疫苗后出现急性血小板减少症。该患者在 6 年前被诊断出患有风湿性多肌痛，在完成 3 个月的低剂量泼尼松疗程后症状缓解且未复发。接种前，患者身体健康；3周前，常规检查显示全血计数无异常，血小板计数为429 × 10 ⁹细胞/升。然而，接种疫苗后 35 天，她出现左侧颞区头痛，鉴于她的风湿性多肌痛病史，她的风湿病学家对可能的巨细胞动脉炎进行了评估。她没有报告风湿性多肌痛症状的复发，并且在实验室评估显示红细胞沉降率为 8 毫米/小时（参考值，0 至 20 毫米/小时）和 C 反应蛋白水平为1.0 毫克/升（参考，<8.0 毫克/升）。然而，同样的评估确实显示了孤立的血小板减少症（血小板计数，115 × 10 ⁹细胞/L），没有其他全血细胞计数异常。患者没有预先存在免疫性血小板减少症的诊断，但经历了短暂的轻度血小板减少症（血小板计数，55 至 110 × 10⁹细胞/L）在前一年急性右耳感染的情况下。鉴于持续头痛和最近接受了腺病毒载体 SARS-CoV-2 疫苗，使用脑磁共振血管造影和肝素 - 血小板因子 4 抗体酶联免疫吸附试验进一步评估了患者，两者都没有显着的发现。测定光密度为 0.057；参考值 <0.400）。患者的头痛最终归因于临时牙桥的咬合外伤引起的牙痛，并在牙科干预后解决。

患者的血小板计数在接种后第 38 天进一步下降至 96 × 10 ⁹细胞/L，然后下降至 59 × 10 ⁹接种后第 42 天的细胞数/升。此时，使用直接、固相、酶联免疫吸附测定法测量针对从血小板表面洗脱的糖蛋白 IIb/IIIa、Ib/IX 和 Ia/IIa 的抗体来评估血小板自身抗体(Versiti)。根据专家建议 (4) 进行了测试，结果显示针对所有 3 种糖蛋白的血小板自身抗体呈阳性，抗糖蛋白 IIb/IIIa 的光密度为 0.119（阈值，≥0.090），抗糖蛋白 Ib/IX 的光密度为 0.180 （阈值，≥0.094），抗糖蛋白 Ia/IIa 为 0.267（阈值，≥0.108）。该测定中每个糖蛋白的光密度阳性阈值设置为正常校准值的两倍（来自健康供体的抗体阴性血浆样本的平均值）。

密切监测患者的血小板计数，显示稳定和快速恢复，无需干预如下：43 天时，56 × 10 ^{9 个}细胞/L；在 44 天时，67 × 10 ^{9 个}细胞/L；在 45 天时，76 × 10 ^{9 个}细胞/升；在 48 天时，143 × 10 ^{9 个}细胞/升；在 51 天时，248 × 10 ^{9 个}细胞/L。血小板计数恢复正常后 3 周重复血小板自身抗体检测；所有 3 种血小板糖蛋白的结果均为阴性。

讨论：血小板自身抗体检测不常规推荐用于疑似免疫性血小板减少症的患者，因为其敏感性适中（约 50%）（5）。然而，当按照专家指南进行糖蛋白特异性抗体检测时，特异性为 90% 至 95% (4, 5)。尽管许多疫苗与血小板减少症有关，但潜在致命性 TTS 的发生可能与针对 SARS-CoV-2 的腺病毒载体疫苗有关。因此，表征这些疫苗接受者新发急性血小板减少症的其他原因的自然史是至关重要的。在这种情况下，患者的初始表现与可能的 TTS 有关，但在进一步评估中，她被发现有短暂的免疫性血小板减少症，并检测到（和类似的短暂）直接糖蛋白特异性血小板自身抗体，这表明接种 Ad26.COV2.S 可能会引起针对血小板糖蛋白或能够与血小板糖蛋白交叉反应的抗体的瞬时产生在某些人身上。如果抗病毒刺突蛋白抗体与血小板糖蛋白发生交叉反应导致这种临床表现，则其他 SARS-CoV-2 疫苗可能会出现由于这种机制导致的血小板减少症。在接种 SARS-CoV-2 疫苗后，血小板自身抗体或抗病毒抗体能够与血小板糖蛋白发生交叉反应的潜在发展是一个值得进一步研究的现象。S 可能会在某些个体中引起针对血小板糖蛋白或能够与血小板糖蛋白发生交叉反应的抗体的瞬时产生。如果抗病毒刺突蛋白抗体与血小板糖蛋白发生交叉反应导致这种临床表现，则其他 SARS-CoV-2 疫苗可能会出现由于这种机制导致的血小板减少症。在接种 SARS-CoV-2 疫苗后，血小板自身抗体或抗病毒抗体能够与血小板糖蛋白发生交叉反应的潜在发展是一个值得进一步研究的现象。S 可能会在某些个体中引起针对血小板糖蛋白或能够与血小板糖蛋白发生交叉反应的抗体的瞬时产生。如果抗病毒刺突蛋白抗体与血小板糖蛋白发生交叉反应导致这种临床表现，则其他 SARS-CoV-2 疫苗可能会出现由于这种机制导致的血小板减少症。在接种 SARS-CoV-2 疫苗后，血小板自身抗体或抗病毒抗体能够与血小板糖蛋白发生交叉反应的潜在发展是一个值得进一步研究的现象。其他 SARS-CoV-2 疫苗可能会发生由于这种机制导致的血小板减少症。在接种 SARS-CoV-2 疫苗后，血小板自身抗体或抗病毒抗体能够与血小板糖蛋白发生交叉反应的潜在发展是一个值得进一步研究的现象。其他 SARS-CoV-2 疫苗可能会发生由于这种机制导致的血小板减少症。在接种 SARS-CoV-2 疫苗后，血小板自身抗体或抗病毒抗体能够与血小板糖蛋白发生交叉反应的潜在发展是一个值得进一步研究的现象。

Hanny Al-Samkari，医学博士

丽贝卡卡普叶，医学博士

Katayoo​​n Goodarzi，医学博士

麻省总医院和哈佛医学院

马萨诸塞州波士顿

参考

• 1. 舒尔茨新罕布什尔州 ,  索沃尔 IH ,  米歇尔森AE , 等. ChAdOx1 nCoV-19 疫苗接种后的血栓形成和血小板减少症。 N Engl J Med。 2021 年；384：2124-30。[PMID：33835768] 做：10.1056/NEJMoa2104882 CrossrefMedlineGoogle Scholar
• 2. 李易杰 ,  电影数据库 ,  格恩斯海默 , 等. 辉瑞和 Moderna SARS-CoV-2 疫苗接种后的血小板减少症。 是 J Hematol。 2021 年；96：534-7。[PMID：33606296] 做：10.1002/ajh.26132 CrossrefMedlineGoogle Scholar
• 3. 布里托 ,  费雷拉 ,  马特乌斯 , 等. 一例 COVID-19 信使核糖核酸疫苗接种后自身免疫性溶血性贫血。 丘疹。 2021 年；13：e15035。[PMID：34150386] 做：10.7759/cureus.15035 CrossrefMedlineGoogle Scholar
• 4. 阿诺德 ,  桑托索 ,  格雷纳赫A ; ISTH血小板免疫科学小组委员会. 在免疫性血小板减少症临床试验中实施血小板自身抗体检测的建议。 J Thromb Haemost。 2012 年；10:695-7。[PMID：22332994] 做：10.1111/j.1538-7836.2012.04664.x CrossrefMedlineGoogle Scholar
• 5. 弗尔宾斯基JR ,  摩尔 JE ,  阿诺德 , 等. 血小板自身抗体检测在免疫性血小板减少症中的敏感性和特异性：诊断检测的系统评价和荟萃分析。 J Thromb Haemost。 2019 年；17:787-94。[PMID：30801909] 做：10.1111/jth.14419 CrossrefMedlineGoogle Scholar