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Researchers Detail More Cases of Clots Tied to COVID Vaccines

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New evidence emerged today tying vaccines for COVID-19 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 combined with a drop in blood platelets after receiving a dose of the AstraZeneca vaccine, which is now called Vaxzevria. They also tested an 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 third 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 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. He was not involved in the research.

Zehnder says that why this syndrome, which seems to be some kind of an autoimmune attack on a blood signaling protein, develops in a small number of people after they get the anticoagulant heparin or a vaccine for COVID-19 is still very much a mystery.

He says that while the catastrophic cases of large clots in areas of the brain where doctors don’t usually see them stand out, he wonders whether other, less obvious cases are going undetected. 

“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.

People who have not been vaccinated can also develop these types of clots, called cerebral venous sinus thrombosis. 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 in vessels that drain blood from the brain for every million people, according to Peter Marks, from the US Food and Drug Administration.

Doctors 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 continued, citing statistics on US COVID cases and deaths maintained by Johns Hopkins University.

In a presentation to the Centers for Disease Control and Prevention 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.

Investigators initially dismissed 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. She 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.

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.

UK Cases

Among the 22 cases identified in the new UK study, 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 the anticoagulant 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.

The UK study authors found that a point-of-care test commonly used to detect HIT — the HemosIL AcuStar HIT IgG assay — was often negative for patients with VITT. They say VITT needs to be confirmed by a different kind of test, an ELISA or enzyme-linked immunosorbent assay.

Patients with VITT also need a different kind of treatment than one would normally give a person experiencing dangerous blood clots or bleeding. Giving platelets, for example, to stop bleeding could make the situation worse. Instead, they need IVIG treatment to mitigate the apparent autoimmune attack. 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.

NEJM. Published online April 16, 2021. Full text, Editorial

Several coauthors report receiving personal fees from one or more of the following companies: Bayer, Bristol Myers Squibb, Daiichi Sankyo, Pfizer, Novartis, Octapharma, Sanofi, Sobi, Alexion, and Takeda. One coauthor reports grants form Shire and Novartis; one coauthor reports other financial relationships with GSK; and one coauthor reports a patent test for bacterial meningitis based on a blood test, filed for patent pending.

Wherry reports consulting agreements with and/or is a scientific advisor for Merck, Roche, Pieris, Elstar, and Surface Oncology. He has a patent licensing agreement on the PD1 pathway with Roche/Genentech and is a founder of Arsenal Biosciences.

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