Fibrinolytic abnormalities in acute respiratory distress syndrome (ARDS) and versatility of thrombolytic drugs to treat COVID‐19

Claire S. Whyte, Gael B. Morrow, Joanne L. Mitchell, Pratima Chowdary, Nicola J. Mutch*

*Corresponding author for this work

Research output: Contribution to journalArticle

14 Citations (Scopus)
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Abstract

The global pandemic of coronavirus disease 2019 (COVID‐19) is associated with the development of acute respiratory distress syndrome (ARDS), which requires ventilation in critically ill patients. The pathophysiology of ARDS results from acute inflammation within the alveolar space and prevention of normal gas exchange. The increase in proinflammatory cytokines within the lung leads to recruitment of leukocytes, further propagating the local inflammatory response.

A consistent finding in ARDS is the deposition of fibrin in the air spaces and lung parenchyma. COVID‐19 patients show elevated D‐Dimers and fibrinogen. Fibrin deposits are found in the lungs of patients due to the dysregulation of the coagulation and fibrinolytic systems. Tissue factor (TF) is exposed on damaged alveolar endothelial cells and on the surface of leukocytes promoting fibrin deposition, while significantly elevated levels of plasminogen activator inhibitor 1 (PAI‐1) from lung epithelium and endothelial cells create a hypofibrinolytic state.

Prophylaxis treatment of COVID‐19 patients with low molecular weight heparin (LMWH) is important to limit coagulopathy. However, to degrade pre‐existing fibrin in the lung it is essential to promote local fibrinolysis. In this review, we discuss the repurposing of fibrinolytic drugs, namely tissue‐type plasminogen activator (tPA), to treat COVID‐19 associated ARDS. tPA is an approved intravenous thrombolytic treatment, and the nebulizer form has been shown to be effective in plastic bronchitis and is currently in Phase II clinical trial. Nebulizer plasminogen activators may provide a targeted approach in COVID‐19 patients to degrade fibrin and improving oxygenation in critically ill patients.
Original languageEnglish
Pages (from-to)1548-1555
Number of pages8
JournalJournal of Thrombosis and Haemostasis
Volume18
Issue number7
Early online date3 Jun 2020
DOIs
Publication statusPublished - Jul 2020

Keywords

  • Fibrinolysis
  • Fibrin
  • Plasminogen Activator Inhibitor 1
  • Tissue plasminogen activator
  • Respiratory distress syndrome (Adult)
  • SARS virus
  • FACTOR XA
  • tissue plasminogen activator
  • MACROPHAGE
  • ACUTE LUNG INJURY
  • PLASMINOGEN-ACTIVATOR INHIBITOR-1
  • respiratory distress syndrome (adult)
  • PNEUMONIA
  • plasminogen activator inhibitor 1
  • INTERLEUKIN-8
  • fibrinolysis
  • ELEVATED LEVELS
  • COAGULATION
  • fibrin
  • EXPRESSION
  • TISSUE FACTOR

ASJC Scopus subject areas

  • Hematology

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