Project Details
Projekt
The role of platelet factor 4, antibodies and platelets in adverse reactions after vaccination against SARS-CoV-2 and in other thrombotic complications
Subject Area
Hematology, Oncology
Term
since 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 514598754
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.
DFG Programme
Research Grants
