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

26 Citations (Scopus)
3 Downloads (Pure)

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
Pages (from-to)2394-2406
Number of pages13
JournalJournal of Thrombosis and Haemostasis
Volume20
Issue number10
Early online date3 Jul 2022
DOIs
Publication statusPublished - 19 Sept 2022

Bibliographical note

Acknowledgements
The authors would like to thank all the patients who consented to be part of this study, and all the staff at the Emergency Department of Aberdeen Royal Infirmary NHS Foundation Trust who looked after these patients, and the patients who consented. We thank the NHS Grampian Biorepository staff, Kristine Nellany, Nadine Hay and Joan Wilson for sample collection, processing and anonymisation and collation of clinical data. We acknowledge the Microscopy and Histology Core
Facility and Dr Neil Scott from the Institute of Applied Health Sciences at the University of Aberdeen for excellent advice and use of the facilities.
Funding
This research was supported by NHS Grampian Endowment (COV19-004 and 20/021), Medical Research Scotland (CVG-1721-20), The University of Aberdeen Development Trust (RG15537), Friends of Anchor (RS 2019 003) and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. CSW and NJM are supported by the British Heart Foundation (PG/15/82/31721; PG/20/17/35050). JGC is supported by NHS Research Scotland. SS receives funding support from the Medical Research Council (MR/T024054/1).

Keywords

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

Fingerprint

Dive into the research topics of 'The suboptimal fibrinolytic response in COVID‐19 is dictated by high PAI‐1'. Together they form a unique fingerprint.

Cite this