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Researchers Seek Cause of Rare Clots Tied to Vaccines

blood cells

April 19, 2021 -- New evidence emerged last week that ties COVID-19 vaccines to extremely rare cases of people who develop blood clots and low platelets within weeks of being vaccinated.

A team of researchers in the United Kingdom conducted an in-depth investigation of 22 patients who developed serious blood clots along with a drop in blood platelets after receiving a dose of the AstraZeneca vaccine, which is now called Vaxzevria. They also tested one additional patient who had clinical signs of a drop in blood platelets after vaccination. Nearly all the patients — 22 of 23 — tested positive for unusual antibodies to platelet factor 4, a signaling protein that helps the body coordinate blood clotting.

The presence of the antibodies suggests that the vaccines are somehow triggering an autoimmune attack that causes large clots to form that then diminish the supply of platelets in the blood.

The study and an editorial on the cases are published in the New England Journal of Medicine.

This is at least the fourth study detailing the presence of these antibodies in patients with blood clots and low platelets after vaccination, and doctors say the emerging evidence suggests that doctors should remain vigilant for this new syndrome in anyone — male or female — who experiences symptoms of blood clots anywhere in the body, not just the brain.

James Zehnder, MD, director of the coagulation laboratory at Stanford University School of Medicine in California, said that the mounting evidence pointing to a "maladaptive immune response" was quite remarkable.

Zehnder says that why this syndrome develops in a small number of people after they get the anticoagulant drug heparin or a vaccine for COVID-19 is still very much a mystery.

He says antibodies against platelet factor 4 are pretty common — about half of people treated with the blood thinner heparin will develop them.

Platelet factor 4 is a protein that is normally tucked away, hidden from the immune system. When platelets rush to the site of an infection or injury, they change their shape, exposing the hidden protein. When platelet factor 4 binds with heparin, the immune system can see it and often makes antibodies against it.

In most people, these antibodies cause no problems. In the “iceberg model” of this mysterious disorder, Zehnder says this is the group that’s hidden deep beneath the surface of the water. No one knows how large this hidden pool of people might be.

Some fraction of the group that develops antibodies will go on to experience a severe drop in platelets, which can lead to bleeding that won’t stop. That group represents the part of the iceberg that sits just below the surface of the water.

A very small fraction will experience a drop in platelets while forming big clots in unexpected places, like the veins that drain blood from the brain. That’s the point of the iceberg that’s sticking out of the water now, he says.

It’s not known what drives people through the process and into crisis. “This provides an interesting opportunity to learn a lot more through that process,” he says.

Even though some of obviously strange cases have been caught, He also wonders about the parts of the iceberg we can’t see.

"Then the question is, you know, how much more of this is going on in a more subtle way? And so I think the true magnitude of it is not known," he says, noting that it will be important in the coming weeks and months to figure out if particular groups of people are at higher risk than others, like young women. "There are many more questions than answers now," he says.

Key Symptoms to Watch

The symptoms to watch for include shortness of breath, headaches, dizziness, muscle weakness, or abdominal pain, back pain, or nausea and vomiting in anyone who is within 3 weeks of their vaccinations, including men.

The most common type of clot linked to the vaccines so far is called a cerebral venous sinus thrombosis (CVST). These cases — whether they happen after a vaccine or not — are extremely rare.

On average each year, there are two to 14 cases of these clots, without a drop in platelets, in vessels that drain blood from the brain for every 1 million people, according to Peter Marks, MD, director of the FDA’s Center for Biologics Evaluation and Research.

When asked how common it might be for a CVST clot to occur with a drop in platelets in people not exposed to vaccines, Marks said it was so rare, he couldn’t even guess.

It’s also important to note, that more is currently known about the clots linked the Vaxzevria vaccine, which is not yet approved for use in the U.S.

In addition to clots in the brain, some patients who had been vaccinated with Vaxzevria also had clots in the veins that drained blood from their liver, legs, and lungs.

Researchers and regulators say that, on the whole, all the vaccines authorized to protect people from the new coronavirus are extremely safe. In fact, the risk of developing a life-threatening blood clot is far higher with COVID than with a vaccine.

"The chances of this happening to you are about between 1 and 100,000 to 1 in 1 million," said John Wherry, PhD, director of the Institute for Immunology at the University of Pennsylvania in Philadelphia. "If you're an American, the chances of dying from COVID are 1 in 600," Wherry said, citing statistics on U.S. COVID cases and deaths maintained by Johns Hopkins University.

Clots After the Johnson & Johnson Vaccine

In a presentation to the CDC this week, representatives of vaccine manufacturer Johnson & Johnson said they'd found a 25-year-old man who developed a rare clot in his brain and low platelets during their clinical trial.

When they went back and tested his stored blood, they found he also had the telltale antibodies to platelet factor 4, making him the 7th known case tied to that vaccine in the United States. He has since recovered.

After the young man had a stroke, Johnson & Johnson paused its clinical trial to gather more information, but ultimately ruled his case as unrelated to the vaccine because another study participant, a 24-year-old woman, also developed a similar blood clot in her brain, but she was in the placebo group. Her case made his seem more likely to be a random event that was unrelated to the vaccine.

The young woman had recently been prescribed birth control pills, which raise a woman's risk for blood clots and strokes like the kind she suffered.

An eighth case, possibly tied to the Johnson & Johnson vaccine, is still under investigation in the United States.

On Friday, Johnson & Johnson pushed back against the idea that adenoviral vector vaccines as a group might be causing the clots.

They said there’s been no issues of clots reported with their Ebola vaccine, which uses the same technology.

Wherry said it's not surprising that these rare cases were not detected in the clinical trials, which involved tens of thousands of people. He said that very rare events sometimes only come to light when a drug or device is used in millions, as the vaccines now have been.

He said that the fact that these events were detected at all means safety surveillance systems are working.

"We're doing everything right," he said. "It's unfortunate and traumatic if it happens, but in terms of risk to benefit ratio, we still have to put the numbers in perspective and now having caught many of these events, we now have an idea of what to do when we see them," Wherry added.

U.K. Cases

Among the 22 cases identified in the new U.K. study that were associated with Vaxzevria, 16 (70%) were under the age of 50, and 14 (61%) were women. All of them were healthy prior to developing the rare clots. None were taking medications linked to clotting or bleeding. Some came in with mild bruising and tiny red spots called petechiae, which indicate bleeding under the skin.

This constellation of symptoms, severe clotting combined with a drop in platelets, is not new. Doctors recognize it as a sign that someone is having a severe and rare reaction to heparin. In patients taking heparin, it's called HIT, for heparin-induced thrombocytopenia.

Doctors investigating the symptoms in the setting of the new COVID vaccines have called it vaccine-induced thrombotic thrombocytopenia, or VITT.

Researchers say that, until more is known, it's also prudent to use anticoagulants other than heparin to treat clots.

Wherry says he's not surprised to be seeing a few men who are affected, but that, so far, the emerging picture suggests that women are at greater risk.

He says women tend to be more prone to autoimmune disease and also are more susceptible to blood clots because of the hormone estrogen.

"So it does fit with this idea that this may be, you know, an indicator of some autoimmune bias," he said.

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