The association of angiostatin and plasminogen plasma levels with Charlson comorbidity burden and mortality in COVID-19.

Abstract

Severe COVID-19 is associated with thrombotic complications. Dysregulated fibrinolysis, marked by increased plasminogen activator inhibitor-1 (PAI-1) and reduced plasmin generation, has been linked to adverse outcomes including death. Plasmin(ogen) is also the precursor of angiostatin, an angiogenesis inhibitor with dual roles both preventing SARS-CoV-2 infection and promoting cell death. While alterations in fibrinolytic markers are associated with disease severity, the relationship between plasminogen and angiostatin with survival outcomes remains unclear. Therefore we compared plasma angiostatin and plasminogen levels between COVID-19 survivors and non-survivors and assessed their association with mortality. The observational cohort study included age- and sex-matched hospitalized COVID-19 survivors and non-survivors. Plasma samples were collected during hospitalization, and angiostatin and plasminogen levels were quantified by immunoblotting. Cox regression, adjusted for Charlson comorbidity score and time from symptom onset to sample collection, assessed their association with mortality. Non-survivors had a higher Charlson score and significantly lower plasma angiostatin and plasminogen levels compared to survivors. Angiostatin was not associated with mortality after multivariate analysis. However, exploratory Kaplan-Meier survival curve analysis suggested that individuals with lowest Charlson score and angiostatin within the lower tertile exhibit lowest survival probability, while individuals with high Charlson score and with angiostatin in the middle tertile exhibit longest survival probability. By contrast, lower plasminogen was independently associated with mortality after adjustments, supporting a role for impaired fibrinolysis in poor outcomes, while a more complex potential association between angiostatin and COVID-19 mortality is emerging consistent with its dual roles in SARS-CoV-2 infection.