Esefeld Max, Handtke Stefan, Kaiser Rainer, Nicolai Leo, Di Fina Lea, Rossaro Dario, Wesche Jan, Rath Justina, Wienrich Ann-Christin, Hoffmann Till, Harasser Lukas, Feistritzer Clemens, Loacker Lorin, Lotfi Kourosh, Holmström Margareta, Antovic Jovan, Steil Leif, Volker Uwe, Ulm Lena, Becker Karsten, Hübner Nils-Olaf, Greinacher Andreas, Thiele Thomas
Universitätsmedizin Greifswald, Greifswald, Germany.
University Medicine Greifswald, Greifswald, Germany.
Blood Adv. 2025 Apr 3. doi: 10.1182/bloodadvances.2024015076.
Thrombosis and Thrombocytopenia syndromes (TTS) describe immune mediated thrombotic adverse reactions following vaccination against Covid-19. Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a well-known sub-entity of TTS, caused by adenovirus vector-based vaccines. VITT is mediated by anti-platelet factor 4 (PF4) IgG-antibodies, activating platelets via Fc-gamma IIa receptors (FcgRIIa). We describe clinical and serological features of 18 patients with anti-PF4/heparin ELISA negative TTS in temporal relationship to mRNA-based Covid-19 vaccination. Symptoms began at a median of 7 (range 1-61) days after vaccination. Patients showed thrombocytopenia (59,000/µl, 0-127,000/µl); petechiae (n=7), venous thromboembolism (n=11), arterial thrombosis (n=6), disseminated intravascular coagulation (n=1), and combined arterial and venous thromboses (n=1). Twelve sera induced FcgRIIa dependent and caspase independent procoagulant activation of platelets indicated by phosphatidylserine exposure and CD62P expression. We found histones precipitated with IgG fractions of TTS sera and antibodies binding to histones were found in 8/12 platelet-activating sera. Ex vivo generated histone/anti-histone IgG complexes strongly activated platelets via FcgRIIa, whereas anti-histone-IgG alone did not. Platelet autoantibodies were detected in 7/12 sera targeting GPIIb/IIIa (n=5); GPIb/IX (n=5) and GPIa/IIa (n=3). However, sera containing platelet anti-GPIIb/IIIa autoantibodies activated also platelets from a Glanzmann patient, making it unlikely that these autoantibodies are causative for platelet activation. Finally, 2/114 healthy vaccinees developed anti-histone antibodies after mRNA-based Covid-19 vaccination. Our data indicate a new sub-entity of TTS associated with platelet activating histone/anti-histone IgG complexes. Further studies are warranted to characterize the biological and clinical role of post-mRNA-based vaccination anti-histone antibodies. SeCo, NCT04370119.
血栓形成和血小板减少综合征（TTS）描述了接种新冠疫苗后免疫介导的血栓性不良反应。疫苗诱导的免疫性血栓性血小板减少症（VITT）是TTS的一个众所周知的亚类，由腺病毒载体疫苗引起。VITT由抗血小板因子4（PF4）IgG抗体介导，通过Fc-γ IIa受体（FcgRIIa）激活血小板。我们描述了18例抗PF4/肝素酶联免疫吸附测定（ELISA）阴性的TTS患者与基于mRNA的新冠疫苗接种存在时间关联的临床和血清学特征。症状在接种疫苗后的中位数为7天（范围1 - 61天）开始出现。患者表现出血小板减少（59,000/µl，0 - 127,000/µl）；瘀点（n = 7）、静脉血栓栓塞（n = 11）、动脉血栓形成（n = 6）、弥散性血管内凝血（n = 1）以及动脉和静脉联合血栓形成（n = 1）。12份血清诱导了FcgRIIa依赖性且不依赖半胱天冬酶的血小板促凝激活，这通过磷脂酰丝氨酸暴露和CD62P表达得以表明。我们发现TTS血清的IgG组分中沉淀有组蛋白，并且在12份激活血小板的血清中有8份发现了与组蛋白结合的抗体。体外生成的组蛋白/抗组蛋白IgG复合物通过FcgRIIa强烈激活血小板，而单独的抗组蛋白-IgG则不会。在12份血清中有7份检测到了针对糖蛋白IIb/IIIa（n = 5）、糖蛋白Ib/IX（n = 5）和糖蛋白Ia/IIa（n = 3）的血小板自身抗体。然而，含有血小板抗糖蛋白IIb/IIIa自身抗体的血清也激活了一名患有血小板无力症患者的血小板，这使得这些自身抗体不太可能是血小板激活的原因。最后，114名健康疫苗接种者中有2名在基于mRNA的新冠疫苗接种后产生了抗组蛋白抗体。我们的数据表明TTS存在一个与血小板激活的组蛋白/抗组蛋白IgG复合物相关的新亚类。有必要进行进一步研究以明确基于mRNA接种后抗组蛋白抗体的生物学和临床作用。SeCo，NCT04370119。
