{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T20:27:10Z","timestamp":1791318430244,"version":"4.3.1"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,3,11]],"date-time":"2022-03-11T00:00:00Z","timestamp":1646956800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Hemostasis and inflammation are both dysregulated in patients with moderate-to-severe coronavirus disease 2019 (COVID-19). Yet, both processes can also be disturbed in patients with other respiratory diseases, and the interactions between coagulation, inflammation, and disease severity specific to COVID-19 are still vague.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Hospitalized patients with acute respiratory symptoms and with severe acute respiratory syndrome coronavirus 2 (SARS-CoV2)-positive (COV<jats:sup>pos<\/jats:sup>) and SARS-CoV2-negative (COV<jats:sup>neg<\/jats:sup>) status were included. We assessed adenosine diphosphate (ADP)-, thrombin receptor activator peptide 6 (TRAP)-, and arachidonic acid (AA)-induced platelet reactivity by impedance aggregometry, as well as leukocyte subtype spectrum and platelet-leukocyte aggregates by flow cytometry and inflammatory cytokines by cytometric bead array.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>ADP-, TRAP-, and AA-induced platelet reactivity was significantly higher in COV<jats:sup>pos<\/jats:sup> than in COV<jats:sup>neg<\/jats:sup> patients. Disease severity, assessed by sequential organ failure assessment (SOFA) score, was higher in COV<jats:sup>pos<\/jats:sup> than in COV<jats:sup>neg<\/jats:sup> patients and again higher in deceased COV<jats:sup>pos<\/jats:sup> patients than in surviving COV<jats:sup>pos<\/jats:sup>. The SOFA score correlated significantly with the mean platelet volume and TRAP-induced platelet aggregability. A larger percentage of classical and intermediate monocytes, and of CD4<jats:sup>pos<\/jats:sup> T cells (T<jats:sub>H<\/jats:sub>) aggregated with platelets in COV<jats:sup>pos<\/jats:sup> than in COV<jats:sup>neg<\/jats:sup> patients. Interleukin (IL)-1 receptor antagonist (RA) and IL-6 levels were higher in COV<jats:sup>pos<\/jats:sup> than in COV<jats:sup>neg<\/jats:sup> patients and again higher in deceased COV<jats:sup>pos<\/jats:sup> patients than in surviving COV<jats:sup>pos<\/jats:sup>. IL-1RA and IL-6 levels correlated with the SOFA score in COV<jats:sup>pos<\/jats:sup> but not in COV<jats:sup>neg<\/jats:sup> patients. In both respiratory disease groups, absolute levels of B-cell-platelet aggregates and NK-cell-platelet aggregates were correlated with <jats:italic>ex vivo<\/jats:italic> platelet aggegation upon stimulation with AA and ADP, respectively, indicating a universal, but not a COVID-19-specific mechanism.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>In moderate-to-severe COVID-19, but not in other respiratory diseases, disease severity was associated with platelet hyperreactivity and a typical inflammatory signature. In addition to a severe inflammatory response, platelet hyperreactivity associated to a worse clinical outcome in patients with COVID-19, pointing to the importance of antithrombotic therapy for reducing disease severity.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2022.844701","type":"journal-article","created":{"date-parts":[[2022,3,11]],"date-time":"2022-03-11T09:48:59Z","timestamp":1646992139000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":22,"title":["Disease Severity in Moderate-to-Severe COVID-19 Is Associated With Platelet Hyperreactivity and Innate Immune 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