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

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.

Keywords: SARS virus; fibrin; fibrinolysis; plasminogen activator inhibitor 1; respiratory distress syndrome (adult); tissue plasminogen activator.

Figure 1

Development of fibrin deposits in the alveolar space. Development of acute respiratory distress syndrome (ARDS) is characterized by the recruitment of inflammatory leukocytes, including neutrophils, macrophages, and monocytes to the pulmonary vasculature and alveolar air space. This leads to a massive insult in the alveolar‐capillary membrane and exudation of fluid rich in cells and plasma proteins, including coagulation factors and fibrinogen. Damage to the endothelial membrane and pulmonary vasculature allows accumulation of coagulation factors within the alveoli. Tissue factor (TF) exposed on the surface of damaged endothelial cells and on the surface of macrophages and monocytes promotes fibrin formation. High levels of tissue necrosis factor β₁ (TNF‐β₁) activate neutrophils to form neutrophil extracellular traps (NETs) and amplify TF exposure on the surface of macrophages and monocytes. Elevated plasminogen activator inhibitor (PAI‐1) expression on the surface of monocytes and macrophages prevents degradation of fibrin deposits by inhibiting tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA)

Figure 2

Fibrin deposition in the lungs during acute respiratory distress syndrome (ARDS) and breakdown by nebulised tissue plasminogen activator (tPA). A, Normal healthy lung with no detectable fibrin deposits. B, During development of ARDS the equilibrium between coagulation and fibrinolysis is disrupted resulting in fibrin deposits in the lung parenchyma and fibrin‐platelet microthrombi in the pulmonary vasculature. This promotes respiratory dysfunction and can lead to a requirement for respiratory support. C, Administration of nebulized tPA will target the bronchioalveolar space tipping the balance of plasminogen activation in favor of fibrinolysis allowing clearance of fibrin from the lung parenchyma thereby improving respiratory function and oxygenation in COVID‐19 patients