The suboptimal fibrinolytic response in COVID‐19 is dictated by high PAI‐1

Claire Whyte, Megan Simpson, Gael B Morrow, Carol Wallace, Alexander J Mentzer, Julian C. Knight, Susan Shapiro, Nicola Curry, Catherine N Bagot, Catherine N Bagot, Henry Watson, James Cooper, Nicola Mutch* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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.
Original languageEnglish
JournalJournal of Thrombosis and Haemostasis
Early online date3 Jul 2022
DOIs
Publication statusE-pub ahead of print - 3 Jul 2022

Keywords

  • COVID-19
  • Fibrin
  • Fibrinolysis
  • PAI-1
  • Vitronectin

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