Early antibody therapy can prevent severe SARS-CoV-2 infection (COVID-19). However, the effectiveness of COVID-19 convalescent plasma (CCP) therapy in treating severe COVID-19 remains inconclusive. To test a hypothesis that some CCP units are associated with a coagulopathy hazard in severe disease that offsets its benefits, we tracked 304 CCP units administered to 414 hospitalized COVID-19 patients to assess their association with the onset of unfavorable post-transfusion D-dimer trends. CCP recipients with increasing or persistently elevated D-dimer trajectories after transfusion experienced higher mortality than those whose D-dimer levels were persistently low or decreasing after transfusion. Within the CCP donor-recipient network, recipients with increasing or persistently high D-dimer trajectories were skewed toward association with a minority of CCP units. In in vitro assays, CCP from higher-risk units had higher cross-reactivity with the spike protein of human seasonal betacoronavirus OC43. Higher-risk CCP units also mediated greater Fcγ receptor IIa signaling against cells expressing SARS-CoV-2 spike compared with lower-risk units. This study finds that post-transfusion activation of coagulation pathways during severe COVID-19 is associated with specific CCP antibody profiles and supports a potential mechanism of immune complex-activated coagulopathy.