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. K E Y W O R D Sfibrin, fibrinolysis, plasminogen activator inhibitor 1, respiratory distress syndrome (adult), SARS virus, tissue plasminogen activatorThis is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

SARS-CoV-2 Spike protein binds to bacterial lipopolysaccharide and boosts proinflammatory activity

“…COVID-19 disease is associated with a major inflammatory component. Increased cytokine and chemokine production in response to virus infection has been the focus of several recent investigations, and patient morbidity and mortality is mainly caused by the severe systemic inflammation and acute respiratory distress syndrome (ARDS) affecting these patients (3,4) although differences in ARDS disease phenotypes are noticed (5).…”

Prognostic Impact of Coagulopathy in Patients with COVID-19: a Meta-analysis of 35 Studies and 6427 Patients

“…Nonetheless, it is paramount to stimulate local brinolysis to degrade pre-existing brin in the lung. Hence, a nebulizer form of tissue-type plasminogen activator to treat COVID-19 has been proposed recently [47] .…”

Fibrinolysis Resistance: A Potential Mechanism Underlying COVID-19 Coagulopathy

“…In those patients, heparin therapy should be carefully monitored and the risk of bleeding should be assessed using, for instance, the HAS-BLED score. 8,9 Oxygenation improvements after r-tPA treatment were recently reported in three patients with COVID-19 and ARDS. 10 How-ever, these observed improvements were only transient, suggesting that the optimal dosing regimen may be higher than usual in COVID-19 and that, in accordance with our own data, response to r-tPA is impaired in COVID-19 patients.…”

“…However, a resistance to t-PA-induced fibrinolysis was already reported in patients with ARDS, who exhibited elevated PAI-1 levels. 8 In these patients, fibrin deposits are found in the lungs due to dysregulation of the coagulation and fibrinolytic systems. 8 These observations suggest that r-tPA could be considered, as a therapeutic approach for COVID-19 in a selected group of patients.…”

“…8 In these patients, fibrin deposits are found in the lungs due to dysregulation of the coagulation and fibrinolytic systems. 8 These observations suggest that r-tPA could be considered, as a therapeutic approach for COVID-19 in a selected group of patients. In those patients, heparin therapy should be carefully monitored and the risk of bleeding should be assessed using, for instance, the HAS-BLED score.…”