Can tPA Be Repurposed to Treat COVID-19 Respiratory Failure?

The clot-busting agent tissue-type plasminogen activator (tPA) may help patients with COVID-19 who are experiencing refractory acute respiratory distress syndrome (ARDS), according to research published ahead of print in the Journal of Trauma and Acute Care Surgery.

The idea to repurpose the drug, a fibrinolytic agent given to patients experiencing heart attack or stroke, is based on evidence that in ARDS, deposition of fibrin in airspaces and lung parenchyma as well as fibrin-platelet microthrombi in the pulmonary vasculature lead to progressive respiratory dysfunction and right heart failure. In the paper, researchers at Massachusetts Institute of Technology (MIT) and the University of Colorado at Denver, note that similar pathologic findings have been documented in lung specimens from patients infected with COVID-19.

Experience in Europe, NYC

“What we are hearing from our intensive care colleagues in Europe and in New York is that many of the critically ill patients with COVID-19 are hypercoagulable, meaning that they are clotting off their IVs, and having kidney and heart failure from blood clots, in addition to lung failure,” said Michael Yaffe, a David H. Koch Professor of Science at MIT in a press release. “There’s plenty of basic science to support the idea that this concept should be beneficial." He states that figuring out appropriate dose and route of administration for the drug requires more time to determine. "But the target we are going after is well-validated.”

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“What we are hearing from our intensive care colleagues in Europe and in New York is that many of the critically ill patients with COVID-19 are hypercoagulable...and having [organ failure] from blood clots, in addition to lung failure."

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Animal experiments, and one human trial, have shown potential benefits of this approach in treating ARDS. In the human trial, performed in 2001, 20 patients who were in respiratory failure following trauma or sepsis were given drugs that activate plasminogen (urokinase or streptokinase, but not tPA). All of the patients in the trial had respiratory distress so severe that they were not expected to survive, but 30% of them survived following treatment.

That is the only study using plasminogen activators to treat respiratory failure in humans to date, largely because improved ventilator strategies have been working well. This appears not to be the case for many patients with Covid-19, Yaffe says.

Ventilator Scarcity

Based on early statistics from Hubei Province, the authors write, the mortality rate for critically COVID-19 patients is 22- 64%. They also point out that, according to the American Hospital Association, as many as 960,000 COVID-19-infected patients may require mechanical ventilation, for which only 62,000 fully-featured ventilators are currently available (based on a 2009 survey). The dwindling supply of ventilators across the country has been well borne out in daily news.

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"...960,000 COVID-19-infected patients may require mechanical ventilation, for which only 62,000 fully-featured ventilators are currently available."
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The significant mortality to be expected among the sickest patients compounded by the potential for a severe shortage of ventilators in the US, the authors say in their paper, point to the emergent need for agents to both treat and attenuate COVID-19-associated respiratory failure and "particularly to salvage patients who have decompensating respiratory status but no access to a mechanical ventilator or extracorporeal membrane oxygenation (ECMO)." 

To test the theory, the team has approval from the Food and Drug Administration’s ‘compassionate use’ program, which allows experimental clinical trials in situations where there are no other treatment options for a patient.

“If it were to work, and we don’t yet know if it will, it has a lot of potential for rapid expansion,” said Dr Yaffe. The approach could be scaled up quickly since every hospital already has tPA in the pharmacy.

“The public health benefits are obvious. We might get people off ventilators quicker, and we could potentially prevent people from needing to go on a ventilator.”

For more COVID-19 coverage for primary care, visit our COVID-19 Resource Page.

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