The role of platelet factor 4, antibodies and platelets in adverse reactions after vaccination against SARS-CoV-2 and in other thrombotic complications

血小板因子 4、抗体和血小板在 SARS-CoV-2 疫苗接种后不良反应和其他血栓并发症中的作用

• 批准号: 514598754
• 负责人: Professor Dr. Andreas Greinacher
• 金额: --
• 依托单位: Abteilung Transfusionsmedizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/514598754?language=en
• 关键词: role; platelet; factor; antibodies; platelets

Vaccination against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) with adenoviral vector-based vaccines can cause unusual thrombosis in combination with thrombocytopenia beginning 5 to 20 days after vaccination. This vaccine-induced immune thrombotic thrombocytopenia (VITT) is associated with high-titer immunoglobulin G (IgG) antibodies directed against the platelet chemokine platelet factor 4 (PF4). Anti-PF4-IgG bound to PF4 activates platelets via platelet FcγIIa receptors. VITT shares close similarities with autoimmune heparin induced thrombocytopenia, a major research focus of our group. Very recently we identified several patients with recurrent thrombosis of unknown cause who have the same antibodies independent of Covid 19 vaccination. We aim to address the pathological immune response against PF4 causing VITT by characterizing the temporal profile of the antibody response in VITT patients. Anti-PF4 IgG from VITT-patients will be analysed for their IgG subclass, clonality and glycosylation status. It is likely that the immune response against PF4 is triggered by the adenoviral component of the vaccine. Hence, binding partners for PF4 in vector-based vaccines, complete vector viruses and other virus species will be identified and compared. Our preliminary data strongly indicate that anti-PF4 antibodies binding to the same epitope on PF4 as in VITT are the cause for severe recurrent thrombosis. We generate an assay facilitating differentiation between HIT-like and VITT-like antibodies. We will further analyse the interaction of adenoviral vectors with megakaryocytes in cell culture and aim to unravel the underlying mechanim of thrombosis and thrombocytopenia occurring 5-20 days after vaccination with mRNA SARS-CoV2 vaccines. The characterisation of the anti-PF4 IgG mediated mechanisms of immunothrombosis in VITT will build the cornerstone of new treatment concepts of patients with VITT, but may also enlight mechanisms of immunothrombosis in patients with Covid 19, where IgG-mediated platelet activation is similarly observed. Finally, we aim to establish a VITT specific mouse model.

针对严重急性呼吸综合征冠状病毒-2（SARS-COV-2）的疫苗接种，基于腺病毒载体的疫苗可能会在疫苗后5到20天开始引起异常血栓形成与血小板减少症。这种疫苗诱导的免疫血栓性血小板减少症（VITT）与针对血小板趋化因子血小板因子4（PF4）的高滴度免疫球蛋白G（IgG）抗体有关。与PF4结合的抗PF4-IGG通过血小板FcγIIA受体激活血小板。 Vitt与自身免疫性肝素诱发的血小板减少症是我们小组的主要研究重点。最近，我们确定了几名患有相同抗体的不明原因血栓形成患者，这些抗体与COVID 19疫苗无关。我们旨在通过表征VITT患者的抗体反应的临时特征来解决针对PF4的病理免疫响应。将分析来自VITT患者的抗PF4 IgG的IgG亚类，克隆性和糖基化状态。针对PF4的免疫响应可能是由疫苗的腺病毒成分触发的。因此，将在基于媒介的疫苗中的PF4的结合伴侣，完整的载体病毒和其他病毒物种进行比较。我们的初步数据强烈表明，与VITT相同的PF4上相同表位结合的抗PF4抗体是导致严重复发性血栓形成的原因。我们将进一步分析细胞培养中腺病毒载体与巨核细胞的相互作用，并旨在揭示用mRNA SARS-COV2疫苗接种后5-20天发生血栓形成和血小板细胞减少症的潜在机制。 VITT中免疫栓塞的抗PF4 IgG介导的机制的表征将建立VITT患者的新治疗概念的基石，但也可能启发IgG 19，IgG介导的血小板激活的患者的免疫神经栓病的机制。最后，我们旨在建立VITT特定的鼠标模型。