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 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-) develop these antibodies. PEA⁺ patients 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 PEA+ patients 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 PEA+ patients. 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.