What we know about the super-rare blood clots linked to the J&J vaccine

Scientists are beginning to unravel what is sparking the rare but severe blood clotting reaction that has now been associated with both the Johnson & Johnson and the AstraZeneca coronavirus vaccines.

Called cerebral venous sinus thrombosis (CVST), this condition occurs when clots form in veins that route blood from the brain, causing strokes or other brain damage. Yesterday federal health officials recommended pausing the use of Johnson & Johnson’s single-shot vaccine after reports that six women in the United States suffered from blood clots in the brain within two weeks of vaccination. One of them died; another is hospitalized in critical condition. The pause comes on the heels of similar reports of CVST in patients in Europe who received the AstraZeneca vaccine.

Blood clots are typically treated with the widely used blood thinner heparin. But that drug can make these vaccine-related clots worse with this syndrome, because the body reacts to heparin in a way that prompts it to make more clots instead of reducing them. That’s why experts say it is vital to distinguish these clots from the more common type and determine what underlying conditions make some people more vulnerable to developing CVST.

Experts stress that people who’ve already gotten the vaccine shouldn’t panic. Nearly seven million Americans have already received a Johnson & Johnson shot, which means these adverse reactions are extremely rare. However, the U.S. Food and Drug Administration advises people who received the Johnson & Johnson vaccine to contact their doctor if they experience severe headaches, serious abdominal pain, leg pain, or shortness of breath, all of which could indicate the presence of blood clots.

“In most cases, there is a clear pattern of serious symptoms—it’s not like, I didn’t sleep well—and there’s a very tight window of about six to 14 days after vaccination, which is very helpful in diagnosing this,” says James Bussel, a pediatric hematologist/oncologist at Weill Cornell Medicine in New York City.

According to current reports, the chance of experiencing this complication is only about one in a million cases, and experts say the benefits still far outweigh the risks of remaining unvaccinated.

Pausing use of the Johnson & Johnson vaccine was done “out of an abundance of caution” and because of the unique treatment that these clots require, according to a joint statement from Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research, and Anne Schuchat, principle deputy director of the Centers for Disease Control and Prevention.

Johnson & Johnson also decided to pause ongoing clinical trials and delay the rollout of their vaccine in Europe while “working closely with medical experts and health authorities” and “reviewing these cases with European health authorities.”

“We want to get this worked out as quickly as we possibly can and that’s why you see the world pause, in other words, you want to hold off for a bit,” Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, said at a media briefing on Tuesday. “We want to leave that up to the FDA and the CDC to investigate this carefully.”

Good news: It’s treatable

When millions of people get vaccines, physicians expect several thousand will develop blood clots. But CVST is such an unusual case, according to Theodore Warkentin, a professor at McMaster University in Ontario, Canada, and an expert on rare clots caused by heparin.

He’s convinced the vaccines are the culprit because of a combination of factors. For one, the complications occurred within a week or two of the shot, and the extremely rare blood clots that formed in the veins that drain blood from the brain are indicative of CVST. Patients are also displaying a dual phenomenon of falling platelet counts while high quantities of antibodies attack the host platelets, a component in the blood that helps with coagulation.

In two scientific papers that appeared last week in the New England Journal of Medicine, a team of European and Canadian scientists evaluated several clotting cases that cropped up in Europe with the AstraZeneca vaccine; one team found this condition resembles an unusual side effect, called heparin-induced thrombocytopenia (HIT), that is triggered by the drug.

Because of the similarity to HIT, researchers are now calling the new disorder “vaccine-induced immune thrombotic thrombocytopenia (VITT).”

“The vaccine is clearly linked to this rare complication,” says Warkentin, who is a coauthor on one of the NEJM papers. “We have a smoking gun.”

We don’t know as yet if there are some genetic determinants or other obvious predispositions that might make people more susceptible to developing this condition. “We know from HIT research that we can’t predict who will develop this disorder,” says Warkentin.

What is known is that it tends to strike younger women. All six patients in the U.S. were women between the ages of 18 and 48, and the vast majority of patients in Europe were less than 60 years old. Experts can’t say for sure, but they do have some clues as to why.

“It is not yet known whether oral contraceptives are the common denominator,” says Nigel Key, director of the hemophilia and thrombosis center at the University of North Carolina School of Medicine. He adds that other possibilities might make women more susceptible to clots, such as previous pregnancies.

Symptoms of VITT are relatively easy to identify, and there is a combination of tests that can determine whether a patient is experiencing this rare blood clot.

A blood test can determine if platelet counts are low, for example, and imaging tests, such as an MRI, can confirm if there is neurological damage. A therapy called intravenous immunoglobulin, a blood product that is used to shore up antibody deficiencies, given with non-heparin anticoagulants could break up the clots.

“This is a serious condition if one gets it, and the severe forms can be quite dangerous,” says Warkentin. “But it is treatable.”

New insights into the real culprit

Researchers are gaining some insights into the mechanism behind the blood clots by studying the similar reactions to the AstraZeneca vaccine, which is formulated using the same technology as the Johnson & Johnson vaccine. As of April 4, EudraVigilance, the European Union’s drug safety database, had reports of 169 total cases of CVST in some 34 million people in Europe and the U.K. who had been vaccinated with the AstraZeneca shot.

It still isn’t clear why one type of vaccine causes these dangerous side effects while the others don’t, although some scientists believe the strategy used by both AstraZeneca and Johnson & Johnson may play a role.

All the current coronavirus vaccines are designed to provoke the immune system into making antibodies against a key protein on SARS-CoV-2, the virus that causes COVID-19. This spike protein sits on the surface of the virus and binds to the ACE2 protein on human cells. Both AstraZeneca and Johnson & Johnson vaccines use fragments of DNA to instruct human cells how to produce the spike protein. Both also use modified cold viruses, called adenoviruses, to deliver these bits of genetic material to the recipient’s cells.

When cells receive the genetic instructions, they churn out spike proteins. The immune system sees the spike proteins as foreign intruders and dispatches antibodies that will recognize the real SARS-CoV-2 viruses and block them from binding and infecting cells. By contrast, the Moderna and Pfizer-BioNTech vaccines use messenger RNA technology to deliver genetic instructions to make the spike protein, and don’t use adenoviruses or DNA.

The clotting syndrome itself is now believed to be triggered by an intense immune system reaction to the vaccine, which somehow prompts the production of antibodies that activate platelets.

“This is such a peculiar constellation of things,” says Alfred Lee, a hematologist and program director for the hematology/oncology fellowship program at the Yale School of Medicine in New Haven, “that it’s probably a real mechanism specific to the vaccines.”