Characterization of anti-platelet factor 4 antibodies and their persistence in vaccine-induced immune thrombotic thrombocytopenia

Abstract

During the COVID-19 pandemic, highly efficacious vaccines were developed to help stop the spread of SARS-CoV-2. The adenoviral vector-based vaccines have caused a rare but serious adverse side effect known as vaccine-induced immune thrombotic thrombocytopenia (VITT). VITT occurs 5 to 30 days after vaccine administration and is characterized by thrombocytopenia and thrombosis. VITT is caused by antibodies against platelet factor 4 (PF4), forming immune complexes that cause platelet activation. This study aims to deepen our understanding of VITT antibody characteristics by investigating anti-PF4 antibody class and subclass distribution, anti-PF4 antibody persistence, and anti-PF4 memory B cell presence in VITT patients. This will improve our understanding of VITT, and disorders caused by anti-PF4 antibodies (anti-PF4 disorders) overall. We hypothesize that anti-PF4 memory B cells cause the persistence and circulation of pathogenic anti-PF4 autoantibodies, but these antibodies change over time, losing their ability to activate platelets and cause thrombosis in VITT patients. We found that IgG is the main antibody class and IgG1 and IgG2 are the main antibody subclasses in VITT, but more work is needed to understand the roles of these antibodies. We also observe that VITT patients continue to produce platelet-activating anti-PF4 antibodies years after VITT diagnosis. These patients have not experienced any recurrent thrombosis or thrombocytopenia, possibly because they have remained on treatment and physicians remain unsure what would happen should they be taken off treatment. We could not definitively detect circulating anti-PF4 memory B cells in VITT patients, so it remains unknown whether immune memory cells play a role in keeping these antibodies around. There is a need to continue to monitor these patients to understand the long-term impacts of this disorder. This work will improve the treatment of patients suffering from anti-PF4 disorders and improve future vaccine safety and efficacy.