Atypical memory B cell clonal expansion and inflammatory programs associate with platelet-activating antibody development in COVID-19.

Patients with COVID-19 who develop platelet-activating antibodies represent a subset at heightened thrombotic risk, yet the immune features associated with this response remains to be defined. We applied single-cell RNA-seq of B and T cells, single B cell V(D)J-seq, and plasma cytokine and chemokine analysis to define immune signatures distinguishing patients who did (PEA+) or did not (PEA-) develop these antibodies. Patients positive for PEA showed prominent transcriptional enrichment of inflammatory, antigen presentation, and B cell receptor signaling pathways within antigen-experienced B cell subsets. Expanded B cell clones in patients positive for PEA were disproportionately enriched within atypical memory B cells and exhibited upregulated IFN-γ-response signatures, increased proliferative mutational patterns, limited class switching, and a significant overrepresentation of RKH/Y5 heavy-chain motifs associated with platelet-activating antibodies, consistent with an extrafollicular-biased response. Parallel T cell profiling revealed IL-12 pathway enrichment across most T cell subsets, increased IFN-γ transcription, and elevated plasma levels of Th1-associated cytokines in patients positive for PEA. Collectively, these data highlight a coordinated inflammatory environment marked by Th1-skewed T cell activation and selective expansion of atypical memory B cell clones carrying RKH/Y5 motifs, defining immunologic features associated with platelet-activating antibody development in COVID-19.