Prothrombotic antibody origin in COVID-19
Despite vaccine development, COVID-19 continues to cause significant morbidity and mortality, with thrombotic complications contributing to severe disease. We previously showed that a subset of hospitalized patients developed prothrombotic platelet-activating antibodies. Here, we used single-cell RNA sequencing of B and T cells, single B-cell V(D)J sequencing, and plasma cytokine and chemokine analysis to define immune signatures distinguishing patients who did (PEA+) or did not (PEA-) form these antibodies. While overall B-cell populations were comparable between groups, PEA+ patients showed robust clonal expansion within extrafollicular (EF) B-cell clusters, enriched for clones bearing structural signatures characteristic of prothrombotic platelet-activating antibodies. The expanded clones in PEA+patients exhibited upregulated IFNgamma signaling and inflammatory gene programs, reduced class switching, and inefficient somatic hypermutation, all supporting an EF B-cell response. In parallel, PEA+ patients exhibited substantial Th1-cell expansion with enrichment of IL-12 and other inflammatory pathways mirroring those observed in the patients' B cells. Plasma cytokine and chemokine analysis confirmed elevation of Th1-associated mediators, including IL-12, in PEA+patients. Together, these convergent findings provide compelling evidence for an immunologic axis whereby IFNgamma produced by IL-12-induced Th1 cells promotes an extrafollicular B-cell response that gives rise to prothrombotic platelet-activating antibodies in COVID-19.