Background <p>Circulating platelets are increasingly recognized for their critical involvement in thromboinflammatory complications during respiratory infections, underscoring the importance of comprehending their dual role in immunomodulation and hemostasis. The multifaceted roles of platelets are attributed to their inherent heterogeneity, where the molecular diversity enables their functional versatility. However, research remains deficient in dissecting platelet heterogeneity within respiratory infection contexts, capturing the platelet subpopulations exhibiting specialized functional roles, and elucidating the therapeutic modulation by dexamethasone and tocilizumab.</p> Methods <p>Leveraging the adequate platelet population detected through single-cell RNA sequencing, this study established stratified study cohorts central to: (1) COVID-19 disease severity, (2) therapeutic responsiveness, and (3) non-COVID-19 respiratory infections. An integrative annotation framework was implemented in this study, which encompassed co-expressed gene module identification, cell-cell communication network mapping, and cell trajectory assessment, to hierarchically dissect the functional dynamics of platelet heterogeneity in disease pathologies and their modulation by therapeutic interventions.</p> Results <p>This study unfolds six severity-associated platelet subpopulations, explores their modulation by corticosteroids and immune antibody treatments, and extends the findings to non-COVID-19 severe conditions. In severe COVID-19, platelet subpopulations with elevated innate immune responsiveness and high coagulation potential are intensively enriched, whereas following dexamethasone administration, this pro-coagulable subpopulation is remarkably repressed. Post-tocilizumab treatment, the instructive interaction from platelets to IFN-activated CD8⁺ T cells is reduced, while communications from memory B cells, CD4⁺ T cells, plasmacytoid dendritic cells, and natural killer cells to platelets are enhanced. A platelet trajectory, which participates in neutrophil chemotaxis and B cell-mediated humoral responses, emerges specifically in COVID-19 conditions and is absent in non-COVID-19.</p> Conclusions <p>A systematic investigation of platelet transcriptomic heterogeneity in respiratory infections, combined with the delineation of its therapeutic modulation by dexamethasone and tocilizumab, advances the understanding of platelet involvement in immune-thrombotic dysregulation and provides a foundation for exploring potential therapeutic targets.</p>