tPA for Refractory ARDS in COVID-19: Clinical Trials Needed to Evaluate Efficacy
In This Article
- Compassionate use of tissue-type plasminogen activator (tPA) has been proposed as salvage therapy for acute respiratory distress syndrome (ARDS) associated with COVID-19
- Current data do suggest that ARDS is associated with a hypercoagulable state
- The recommendation for tPA is based on a single safety trial of urokinase in severe ARDS and a meta-analysis of 22 studies of plasminogen activators in animal models of acute lung injury
- There is an absence of data on whether therapeutic anticoagulation or a fibrinolytic will improve outcomes in patients with COVID-19; clinical trials are needed to evaluate efficacy
On March 20, 2020, a special report in the Journal of Trauma and Acute Care Surgery proposed compassionate use of tissue-type plasminogen activator (tPA) as salvage therapy for acute respiratory distress syndrome (ARDS) associated with COVID-19. In a fast literature update posted on March 31, Rebecca Israel, MD, a research fellow in medicine at Massachusetts General Hospital, explained why clinical trials are needed in order to evaluate the efficacy of tPA.
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Hypercoagulability and ARDS Generally
Multiple studies have demonstrated decreased levels of anticoagulant proteins and increased expression of procoagulant proteins and anti-fibrinolytic factors in patients with ARDS. This hypercoagulable environment seems to favor the formation of fibrin deposits in the airspaces and vasculature that promote lung injury.
Hypercoagulability and ARDS Associated with COVID-19
Three tissue samples from COVID-19 patients (two lung biopsies and an autopsy sample from a patient who died of ARDS) have been reported to demonstrate fibrinous exudate within the alveoli and occlusion of small pulmonary vessels. This suggests a hypercoagulable state similar to that described in ARDS from other causes.
Multiple large case series have demonstrated a relationship between severe COVID-19 and coagulation abnormalities. In fact, two of them reported an association between elevated d-dimer, prothrombin time, development of ARDS and mortality from ARDS.
Anticoagulants and Fibrinolytics as Treatment for ARDS
To date, no trial has detected significant clinical benefits of an anticoagulant in ARDS. The recommendation for tPA is based on one phase I trial of urokinase in 20 patients with severe ARDS and a meta-analysis of 22 studies of plasminogen activators in animal models of acute lung injury. None of these studies evaluated the impact of a fibrinolytic on viral pneumonia.
Management of COVID-19 should focus on evidence-based interventions with strong biologic plausibility. Prophylactic anticoagulation, a mainstay of management for critically ill patients, is appropriate because it reduces the risk of deep vein thrombosis and may have a secondary benefit for the lungs. Clinical trials are needed in order to evaluate the efficacy of tPA in ARDS.
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