Suppression of fibrinolysis and hypercoagulability link lung injury and mortality in severe COVID-19

ABSTRACT

Background: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is marked by coagulopathy that may relate to disease severity. Aims: We sought to understand the link between coagulopathy and acute respiratory distress syndrome (ARDS) in critically ill patients with Coronavirus Disease 2019 (COVID-19). Methods: We prospectively evaluated coagulation factor-specific biomarkers by ELISA and activity assays, viscoelastic testing by rotational thromboelastometry (ROTEM), and clinical data in 56 critically ill patients with COVID-19. One and two-way analyses of variance were performed to uncover association of factor levels with mortality, ECMO-requirement, major thrombotic events, and ARDS severity by PaO2/FiO2 ratio. Results: Patients averaged 57.2 years in age. Twenty-five percent had a major thromboembolic event, 16% had a major hemorrhage, and 23% died. All patients displayed hypercoagulability on viscoelastic testing, although those requiring veno-venous extracorporeal membrane oxygenation (ECMO) also had signs of consumptive coagulopathy and more frequent hemorrhagic complications than ECMO-naïve patients. In all patients, plasminogen activator inhibitor-1 (PAI-1) levels were increased, and ROTEM-determined clot lysis limited despite increased D-dimer levels, consistent with fibrinolytic suppression. In patients with thromboembolic events, regardless of ECMO status, PAI-1, von Willebrand Factor (vWF), and factor VIII levels were elevated. Increased PAI-1 and vWF and decreased ADAMTS13 levels correlated with ARDS severity and mortality. Conclusions: Our study defines the relationship between COVID-19 associated coagulopathy and the severity of acute lung injury by describing elevation in markers of endotheliopathy in association with low PaO2/FiO2 ratios. We identified increased PAI-1 with ARDS severity and thrombotic events, implicating fibrinolytic suppression in the microcirculatory injury and subsequent micro-and macrovascular thrombosis of severe COVID-19. Further investigation into therapeutic approaches to limit endothelial injury is needed. Other items for consideration The study was approved by the Duke Institutional Review Board (Pro00101196 and Pro00105315).