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Off-label use of tissue plasminogen activator (tPA) for COVID-19 patients with acute respiratory distress syndrome (ARDS) improved lung function in a case series.

Among three patients treated with an intermediate dose of alteplase (Activase), the ratio of partial pressure of arterial oxygen to percentage of inspired oxygen (PaO2/FiO2, or P/F) improved by 38% to almost 100%, found Christopher Barrett, MD, of Beth Israel Deaconess Medical Center and Harvard in Boston, and colleagues.

However, those improvements proved temporary for two of the three and were lost over time after completion of tPA despite receiving heparin afterward, the group reported in the.

Other groups have also described using tPA in desperate cases in recent days, to mixed success.

Mount Sinai Hospital physicians in New York City saw the bolus but then diminish again, presumably as clots reformed, for one patient treated there with tPA, while another three saw a more durable improvement in oxygenation.

Sukh Nijjer, MD PhD, of Imperial College London, tweeted about his giving alteplase to an ST-segment elevation myocardial infarction patient with COVID-19 when emergency angioplasty and stenting was not possible: "Amazingly O₂ requirements also reduced & improved clinical status."

A higher dose of tPA, like that used in heart attacks or for pulmonary embolism, might be reasonable, Barrett's group suggested.

Using a "larger bolus-dose tPA (50 mg or 100 mg bolus) without holding anticoagulation in order to prevent recurrence of the suspected pulmonary microvascular thrombosis underlying COVID-19 ARDS is worthy of further consideration and study," they wrote.

Patients seem to get more durable responses when simultaneously on heparin while getting tPA, Barrett noted in an email to 麻豆传媒.

Coagulopathy has emerged as a hallmark of severe COVID-19. One study showed that 71.4% who died from the virus met ISTH criteria for disseminated intravascular coagulation, compared with only 0.6% of survivors.

The same group had argued the for tPA in COVID-19 in the Journal of Trauma and Acute Care Surgery last month, noting that clotting problems have been seen in ARDS from other causes.

"A consistent finding in ARDS is the deposition of fibrin in the airspaces and lung parenchyma, along with fibrin-platelet microthrombi in the pulmonary vasculature, which contribute to the development of progressive respiratory dysfunction and right heart failure," they noted.

They had used 25-mg IV tPA bolus over 2 hours, followed by a 25-mg infusion over the subsequent 22 hours for the critically-ill, mechanically-ventilated COVID-19-positive patients with ARDS. Extracorporeal membrane oxygenation capabilities, staffing, and resources were extremely limited at the center due to pandemic, the group noted.

They are using the early results to move forward with a compassionate use clinical trial, along with looking for biomarkers of enhanced response.

"We're hearing anecdotally that a subset of patients with COVID-19 induced ARDS are clotting abnormally around their catheters and IV lines," co-author Michael Yaffe, MD, PhD, of Beth Israel Deaconess, said in a . "We suspect these patients with aggressive clotting are will show the most benefit from tPA treatment, and this new clinical trial will reveal whether that's the case."

However, now is not the time to start widely using tPA for COVID-19, cautioned Stephan Moll, MD, of the University of North Carolina at Chapel Hill Hemophilia and Thrombosis Center.

"We are always concerned about the risk of bleeding," he told 麻豆传媒. Critically-ill COVID-19 patients can have prolongation of partial thromboplastin time, renal failure, and other risk factors for bleeding, he noted, so giving them thrombolysis needs to be weighed carefully.

The temporary benefits seen in Barrett's case series might suggest more aggressive anticoagulation to prevent recurrence of clots after tPA dissolves those already present, Moll noted.

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