Weiss, Alvarez & Chen et al
Mar 17, 2025
This study investigated why COVID-19 convalescent plasma (CCP) therapy has shown inconclusive efficacy in treating severe COVID-19.
This study explored why COVID-19 convalescent plasma (CCP) therapy has shown inconsistent benefits in severe cases, hypothesizing that certain CCP units may trigger coagulopathy, offsetting any beneficial therapeutic effects imparted by neutralizing antibody activity. We tracked 304 CCP units given to 414 hospitalized patients and analyzed post-transfusion D-dimer levels, a marker of coagulation.
Key Findings:
Elevated D-dimer levels post-CCP therapy were linked to mortality: Patients with increasing or persistently high D-dimer levels post-transfusion had higher mortality (52–61%) than those with low or decreasing levels (24–38%).
Donor CCP-specific risk: Adverse D-dimer trajectories clustered non-randomly around CCP from a subset of donors (“high-risk CCP”).
Antibody cross-reactivity: High-risk CCP had elevated IgG cross-reactive to the seasonal betacoronavirus OC43 spike protein, with a higher anti-OC43 to anti-SARS-CoV-2 antibody ratio.
Enhanced FcγRIIa signaling: High-risk CCP triggered stronger FcγRIIa signaling against SARS-CoV-2 and OC43 spike proteins, suggesting immune complex–mediated coagulopathy.
Neutralization activity was not associated with protection: Neutralizing activity and total anti-SARS-CoV-2 antibody levels were similar between high- and low-risk CCP.
Anti-IFN Autoantibodies were rare: Only one CCP sample had anti–IFN-ω autoantibodies, and it was not linked to high D-dimer levels.
Implications:
CCP heterogeneity may explain inconsistent results in clinical trials, with some units causing harm through non-neutralizing antibody functions.
Cross-reactive antibodies, especially to OC43, may contribute to coagulation via FcγR signaling, underscoring the importance of antibody specificity.
Future therapies should account for donor antibody profiles beyond neutralization.
Donor-recipient network analysis offers a novel method to assess heterogeneity in plasma therapy outcomes.
Conclusion:CCP units with cross-reactive anti-OC43 antibodies and enhanced FcγRIIa signaling may promote coagulation and adverse outcomes in severe COVID-19. Understanding antibody functionality and donor variability is critical for optimizing plasma-based therapies.