Disease Severity in Moderate-to-Severe COVID-19 Is Associated With Platelet Hyperreactivity and Innate Immune...

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.

Hospitalized patients with acute respiratory symptoms and with severe acute respiratory syndrome coronavirus 2 (SARS-CoV2)-positive (COV^pos) and SARS-CoV2-negative (COV^neg) 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.

ADP-, TRAP-, and AA-induced platelet reactivity was significantly higher in COV^pos than in COV^neg patients. Disease severity, assessed by sequential organ failure assessment (SOFA) score, was higher in COV^pos than in COV^neg patients and again higher in deceased COV^pos patients than in surviving COV^pos. 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^pos T cells (T_H) aggregated with platelets in COV^pos than in COV^neg patients. Interleukin (IL)-1 receptor antagonist (RA) and IL-6 levels were higher in COV^pos than in COV^neg patients and again higher in deceased COV^pos patients than in surviving COV^pos. IL-1RA and IL-6 levels correlated with the SOFA score in COV^pos but not in COV^neg patients. In both respiratory disease groups, absolute levels of B-cell-platelet aggregates and NK-cell-platelet aggregates were correlated with ex vivo platelet aggegation upon stimulation with AA and ADP, respectively, indicating a universal, but not a COVID-19-specific mechanism.

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.