Blood clots leave clinicians with clues about Covid-19 — but no proven treatments

Doctors treating the sickest Covid-19 patients have zeroed in on a new phenomenon: Some people have developed widespread blood clots, their lungs peppered with tiny blockages that prevent oxygen from pumping into the bloodstream and body.

A number of doctors are now trying to blast those clots with tPA, or tissue plasminogen activator, an antithrombotic drug typically reserved for treating strokes and heart attacks. Other doctors are eyeing the blood thinner heparin as a potential way to prevent clotting before it starts.

Without a rigorous study, though, it’s impossible to know the potential risks or benefits of tPA, blood thinners, or other drugs — or what makes a difference. Until more robust research gets underway, the body of evidence now is a handful of case reports and anecdotal observations on the use of drugs to combat clots.

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“I can’t stress enough that it is important to have a controlled study to demonstrate that people who get this either do or don’t do better,” said Christopher Barrett, a senior surgical resident at Beth Israel Deaconess Medical Center, a research fellow at MIT and co-author of case reports recently published on blood clots in Covid-19 patients.

As with so much else about the Covid-19 response, health experts are learning about the symptom on the fly. Blood clots are common in patients who are immobilized, but they seem to be smaller and cause far more severe damage in some Covid-19 patients. Doctors have said they see patients with blood clots forming not only in their lungs, but also in blood vessels. Autopsies have also revealed blood clots in kidneys and other organs, which some experts say suggests an overwhelming immune system response to the virus that inflicts harm on the body.

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Physicians from the U.S., the Netherlands, and China have published a number of case reports in scientific journals about Covid-19 patients with a multitude of small blood clots. In one report, researchers in China said 7 out of 10 patients who died of Covid-19 had small blood clots throughout the bloodstream, compared to fewer than 1 in 100 people who survived. Some of the patients in those case reports received blood thinners or tPA, sometimes when there seemed to be nothing else to try. Some survived, some did not.

“This is a real-time learning experience,” said Clyde Yancy, chief of cardiology at Northwestern University Feinberg School of Medicine.

“I don’t think any of us can declare anything definitively, but we know from the best available data that about one-third of patients who have Covid-19 infections do in fact have evidence of thrombotic disease,” he added. Yancy said there is early-stage, preliminary evidence to suggest that a regimen of anti-coagulants used as a preventive tool could reduce the number of clotting episodes a patient experiences.

It still isn’t clear why the virus leads to these blood clots forming, or why patients’ bodies can’t break them up. It also isn’t clear how significant a role they play in a patient’s illness. Those questions will take time to answer, Barrett said.

But there remains a need for treatments that can buy time to help people fight the virus.

“It’s not necessarily the virus killing people, it’s the organ failure that happens as a result of the viral infection,” Barrett said. “If you can support people through their organ failure, … the immune system will eventually clear out the virus.”

The three patients in Barrett’s case reports, all of whom were on ventilators to help them breathe, initially did better when they were given tPA in what’s known as off-label use in salvage therapy. One of them died, one of them improved briefly, and one of them had a durable response, he said.

Barrett is part of a group awaiting approval from the Food and Drug Administration to move forward with a randomized clinical trial to determine what if any role tPA might play. The trial they hope to conduct at three hospitals in Colorado, one in Massachusetts, and one in New York will give people the drug when they are not as sick as the people in the case reports, who had exhausted all other treatments. Patients will be randomly assigned to receive the drug or a placebo; the trial will also test different dosing.

“We really need the data to prove or disprove that it’s working.”

Hunter Moore, transplant surgery fellow at University of Colorado, Denver

“Until then, we’re kind of handicapped,” said Hunter Moore, a transplant surgery fellow at the University of Colorado, Denver, and a researcher working on the trial with Barrett. Now, he said, “it’s all based on off-label use and it’s kind of hearsay in terms of how it’s done. So we really need the data to prove or disprove that it’s working.”

Doctors around the country are already giving patients heparin or tPA. Many reached out to Moore and Barrett after reading their case reports, hoping to try tPA on their own patients. At Mount Sinai Hospital in New York, five patients were given tPA, with mixed results, according to an Associated Press story that sparked strong reactions among some. Former FDA Commissioner Scott Gottlieb has called for more comprehensive research on the subject — which Moore and Barrett’s proposed study could provide.

The drug tPA does carry its own risk. It’s typically given to stroke patients within hours of symptoms to reduce the risk of bleeding in the brain. But Moore pointed out that the risk of those bleeds for patients on tPA is lower than for Covid-19 patients who are placed on ECMO machines to improve oxygen levels in their blood.

Yancy of Northwestern said any studies on blood clots will contribute to the picture of how cardiovascular conditions heighten the danger of Covid-19 infections. That, too, could shed light on the disproportionate burden on African Americans, whose infection rate is threefold higher than other Americans’ and whose death rate is sixfold higher.

Risk factors for Covid-19 infection such as hypertension, diabetes, obesity, and preexisting cardiovascular disease — all of which are more common in African Americans — tip the scales toward more serious illness. Socioeconomic factors that make it harder for some people to work from home also likely play a part. Blood clotting may be one more key factor.

“The reason for the increased infection rate likely has very little to do with race [but] more to do with the life and living circumstances for African Americans,” Yancy said.


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