Abstract
Background: Severe COVID-19 disease is associated with thrombotic complications and extensive fibrin deposition. This study investigates whether the hemostatic complications in COVID-19 disease arise due to dysregulation of the fibrinolytic system.
Methods: This prospective study analyzed 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 plasminogen activator inhibitor-1 (PAI-1)/plasmin activity using chromogenic substrates. Clot structure was visualized by confocal microscopy.
Results: PAI-1 and its cofactor, vitronectin, are significantly elevated in patients with COVID-19 disease compared with those with non-COVID-19 respiratory infection and healthy control groups. Thrombin activatable fibrinolysis inhibitor and tissue plasminogen activator were elevated in patients with COVID-19 disease relative to healthy controls. PAI-1 and tissue plasminogen activator (tPA) were associated with more severe COVID-19 disease severity. Clots formed from COVID-19 plasma demonstrate an altered fibrin network, with attenuated fiber 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.
Conclusion: This study shows 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 possibility of using pre-existing drugs, such as tenecteplase, to treat COVID-19 disease and potentially other respiratory diseases.
Keywords: COVID-19; PAI-1; fibrin; fibrinolysis; vitronectin.
【저자키워드】 COVID-19, fibrinolysis, PAI-1, FIBRIN, vitronectin., 【초록키워드】 Hospitalized, severity, Prospective Study, variant, drugs, respiratory diseases, ELISA, COVID-19 disease, respiratory infection, Patient, Complication, plasma, prognostic, inhibitor, disease, severe COVID-19 disease, dysregulation, cofactor, confocal microscopy, Non-COVID-19, fibrinolytic system, profile, healthy control, fibrinolytic, healthy controls, treat, substrates, clot, fiber, thrombotic complication, highlight, tissue plasminogen activator, analyzed, significantly, elevated, faster, correlated, reveal, groups, quantified, attenuate, 113 patient, COVID-19 sample, patients with COVID-19, with COVID-19, 【제목키워드】 fibrinolytic,