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.

以腺病毒载体为基础的疫苗接种严重急性呼吸综合征冠状病毒-2(SARS-CoV-2)可引起罕见的血栓形成，并在接种后5至20天开始伴有血小板减少。疫苗诱导的免疫性血栓性血小板减少症(VITT)与针对血小板趋化因子4(PF4)的高效价免疫球蛋白G(Ig G)抗体有关。与PF4结合的抗PF4Ig G通过血小板FcγIIa受体激活血小板。Vitt与自身免疫性肝素引起的血小板减少症有密切的相似之处，这是我们小组的主要研究重点。最近，我们发现了几名原因不明的复发性血栓形成患者，他们的抗体与接种Covid19疫苗无关。我们的目标是通过描述VITT患者抗体反应的时间特征来研究针对PF4引起的VITT的病理免疫反应。将分析来自VITT患者的抗PF4Ig G的Ig G亚类、克隆性和糖基化状态。针对PF4的免疫反应很可能是由疫苗中的腺病毒成分触发的。因此，将识别和比较载体疫苗、全载体病毒和其他病毒物种中PF4的结合伙伴。我们的初步数据有力地表明，抗PF4抗体与PF4上的相同表位结合是严重复发血栓形成的原因。我们制作了一种有助于区分Hit-Like和Vitt-Like抗体的方法。我们将进一步分析腺病毒载体与巨核细胞在细胞培养中的相互作用，旨在揭示SARS-CoV2基因疫苗接种后5-20天发生血栓形成和血小板减少的潜在机制。对抗PF4-Ig G介导的VITT免疫血栓形成机制的鉴定将为VITT患者的新治疗理念奠定基础，同时也可能揭示Covid 19患者的免疫血栓形成机制，在Covid 19患者中观察到类似的Ig G介导的血小板激活。最后，我们的目标是建立一种维生素T特异的小鼠模型。