The suboptimal fibrinolytic response in COVID-19 is dictated by high PAI-1.
Whyte CS., Simpson M., Morrow GB., Wallace CA., Mentzer AJ., Knight JC., Shapiro S., Curry N., Bagot CN., Watson H., Cooper JG., Mutch NJ.
BACKGROUND: Severe COVID-19 disease is associated with thrombotic complications and extensive fibrin deposition. Here, we investigate whether the haemostatic complications in COVID-19 disease arise due to dysregulation of the fibrinolytic system. METHODS: This prospective study analysed fibrinolytic profiles of 113 patients hospitalized with COVID-19 disease with 24 patients with non-COVID-19 respiratory infection and healthy controls. Antigens were quantified by Ella™ system or ELISA, clot lysis by turbidimetric assay, and PAI-1/plasmin activity using chromogenic substrates. Clot structure was visualised by confocal microscopy. RESULTS: PAI-1 and its cofactor, vitronectin, are significantly elevated in COVID-19 disease compared to non-COVID-19 respiratory infection and healthy control groups. Thrombin activatable fibrinolysis inhibitor and tissue plasminogen activator were elevated in COVID-19 disease relative to healthy controls. PAI-1 and tPA were associated with more severe COVID-19 disease severity. Clots formed from COVID-19 plasma demonstrate an altered fibrin network, with attenuated fibre length and increased branching. Functional studies reveal that plasmin generation and clot lysis were markedly attenuated in COVID-19 disease, while PAI-1 activity was elevated. Clot lysis time significantly correlated with PAI-1 levels. Stratification of COVID-19 samples according to PAI-1 levels reveals significantly faster lysis when using the PAI-1 resistant tPA variant, Tenecteplase, over Alteplase lysis. DISCUSSION: We demonstrate that the suboptimal fibrinolytic response in COVID-19 disease is directly attributable to elevated levels of PAI-1 which attenuate plasmin generation. These data highlight the important prognostic potential of PAI-1 and the potential to utilise pre-existing drugs, such as Tenecteplase to treat COVID-19 disease and potentially other respiratory diseases.