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The suboptimal fibrinolytic response in COVID-19 is dictated by high PAI-1
Claire S Whyte1, Megan Simpson1, Gael B Morrow1,2,3
1Aberdeen Cardiovascular & Diabetes Centre, School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK.
Insights
Severe COVID-19 is linked to blood clot issues due to impaired fibrinolysis. Elevated plasminogen activator inhibitor-1 (PAI-1) in COVID-19 patients significantly reduces clot breakdown, suggesting PAI-1 as a therapeutic target.
Area of Science:
- Hematology
- Infectious Diseases
- Cardiovascular Research
Background:
- Severe COVID-19 is associated with thrombotic complications and fibrin deposition.
- This study investigates the role of fibrinolytic system dysregulation in COVID-19 hemostatic complications.
Purpose of the Study:
- To analyze fibrinolytic profiles in COVID-19 patients.
- To determine the relationship between fibrinolysis markers and COVID-19 severity.
- To explore the impact of elevated PAI-1 on clot structure and lysis in COVID-19.
Main Methods:
- Prospective study of 113 COVID-19 patients, 24 non-COVID-19 respiratory infection patients, and healthy controls.
- Quantification of fibrinolytic antigens (PAI-1, vitronectin, TAFI, tPA) and plasmin activity.
- Assessment of clot lysis, fibrin structure via microscopy, and correlation with disease severity.
Main Results:
- Significantly elevated PAI-1 and vitronectin in COVID-19 patients compared to controls.
- Increased thrombin activatable fibrinolysis inhibitor and tissue plasminogen activator (tPA) in COVID-19 patients.
- Attenuated plasmin generation and clot lysis in COVID-19 plasma, correlated with higher PAI-1 levels and altered fibrin structure.
Conclusions:
- Suboptimal fibrinolysis in COVID-19 is attributed to elevated PAI-1, which inhibits plasmin generation.
- PAI-1 levels have prognostic potential in COVID-19.
- Existing drugs like tenecteplase may offer therapeutic benefits for COVID-19 and other respiratory diseases.
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.
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