The role of platelet factor4, antibodies and platelets in adverse reactions after vaccination against SARS-CoV-2 and in other thrombotic complications

Vaccination against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) with adenoviral vector-based vaccines can cause unusual thrombosis combined with thrombocytopenia starting 5 to 20 days after vaccination. This vaccine-induced immune thrombotic thrombocytopenia (VITT) is associated with high-titre 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 heparin-induced autoimmune thrombocytopenia, an important research focus of our group. We recently identified several patients with recurrent thrombosis of unknown origin, who have the same antibodies independently of a Covid-19 vaccination. Our goal is to address the pathologic immune response against PF4 that causes VITT by characterizing the temporal profile of the antibody response in VITT patients. Anti-PF4 IgG from VITT patients will be analyzed for their IgG subclass, clonality and glycosylation status. It is likely that the immune response against PF4 is elicited by the adenoviral component of the vaccine. Therefore, binding partners for PF4 in vector-based vaccines, whole vector viruses, and other virus species will be identified and compared. Our preliminary data strongly suggest that anti-PF4 antibodies binding to the same epitope on PF4 as in VITT are the cause of severe recurrent thrombosis. We generate an assay, which facilitates the differentiation between HIT-like and VITT-like antibodies. We will further analyze the interaction of adenoviral vectors with megakaryocytes in cell culture and aim to unravel the underlying mechanism of thrombosis and thrombocytopenia occurring 5-20 days after vaccination with mRNA SARS-CoV2 vaccines. The characterization of the anti-PF4 IgG-mediated mechanisms of immune thrombosis in VITT will lay the foundation for new treatment concepts of patients with VITT, but may also help to elucidate the mechanisms of immune thrombosis in patients with Covid 19, in whom IgG-mediated platelet activation similarly observed. Finally, we want to establish a VITT-specific mouse model. We will further analyze the interaction of adenoviral vectors with megakaryocytes in cell culture and aim to unravel the underlying mechanism of thrombosis and thrombocytopenia occurring 5-20 days after vaccination with mRNA SARS-CoV2 vaccines. The characterization of the anti-PF4 IgG-mediated mechanisms of immune thrombosis in VITT will lay the foundation for new treatment concepts of patients with VITT, but may also help to elucidate the mechanisms of immune thrombosis in patients with Covid 19, in whom IgG-mediated platelet activation similarly observed. Finally, we want to establish a VITT-specific mouse model. We will further analyze the interaction of adenoviral vectors with megakaryocytes in cell culture and aim to unravel the underlying mechanism of thrombosis and thrombocytopenia occurring 5-20 days after vaccination with mRNA SARS-CoV2 vaccines. The characterization of the anti-PF4 IgG-mediated mechanisms of immune thrombosis in VITT will lay the foundation for new treatment concepts of patients with VITT, but may also help to elucidate the mechanisms of immune thrombosis in patients with Covid 19, in whom IgG-mediated platelet activation similarly observed. Finally, we want to establish a VITT-specific mouse model. to unravel the underlying mechanism of thrombosis and thrombocytopenia occurring 5-20 days after vaccination with mRNA SARS-CoV2 vaccines. The characterization of the anti-PF4 IgG-mediated mechanisms of immune thrombosis in VITT will lay the foundation for new treatment concepts of patients with VITT, but may also help to elucidate the mechanisms of immune thrombosis in patients with Covid 19, in whom IgG-mediated platelet activation similarly observed. Finally, we want to establish a VITT-specific mouse model. to unravel the underlying mechanism of thrombosis and thrombocytopenia occurring 5-20 days after vaccination with mRNA SARS-CoV2 vaccines. The characterization of the anti-PF4 IgG-mediated mechanisms of immune thrombosis in VITT will lay the foundation for new treatment concepts of patients with VITT, but may also help to elucidate the mechanisms of immune thrombosis in patients with Covid 19, in whom IgG-mediated platelet activation similarly observed. Finally, we want to establish a VITT-specific mouse model. The characterization of the anti-PF4 IgG-mediated mechanisms of immune thrombosis in VITT will lay the foundation for new treatment concepts of patients with VITT, but may also help to elucidate the mechanisms of immune thrombosis in patients with Covid 19, in whom IgG-mediated platelet activation similarly observed. Finally, we want to establish a VITT-specific mouse model. The characterization of the anti-PF4 IgG-mediated mechanisms of immune thrombosis in VITT will lay the foundation for new treatment concepts of patients with VITT, but may also help to elucidate the mechanisms of immune thrombosis in patients with Covid 19, in whom IgG-mediated platelet activation similarly observed. Finally, we want to establish a VITT-specific mouse model.