By Carolyn Y. Johnson

When an otherwise healthy 48-year-old Nebraska woman arrived at an emergency room after three days of abdominal pain and malaise, doctors discovered a life-threatening puzzle. Her platelets, the colorless blood cells that clump to form clots, had plummeted. But a CT scan of her abdomen and pelvis revealed extensive blood clots.

Her medical team raced to untangle the seemingly paradoxical combination of symptoms. Even as they treated the patient with a common blood thinner, more clots appeared — in her brain and in the blood vessels around her liver and spleen.

As doctors scoured the patient’s medical history for clues, a seemingly innocent fact emerged: She had received the Johnson & Johnson coronavirus vaccine two weeks before starting to feel ill.

Between March 19 and April 12, medical teams from Virginia to Nevada encountered the same baffling constellation of symptoms in five other women between the ages of 18 and 48. All had recently received the Johnson & Johnson vaccine. One woman died.

Last Tuesday, U.S. health officials recommended that those vaccinations be paused so experts could reconsider how, or if, the vaccine could be safely used. There were only six known cases among more than 7 million shots, but the symptoms drew alarm because they were severe and the women were otherwise healthy. They also struck an ominous resemblance to cases in Europe among people who received a similar coronavirus shot developed by Astra­Zeneca and the University of Oxford.

Making sense of rare, possibly related adverse events after vaccination can be notoriously tricky, but in this case, U.S. health officials have a blueprint. European scientists’ detective work on similar cases in March, paired with decades of painstaking research into an obscure immune reaction to the anticoagulant drug heparin, have given them a probable — but not certain — mechanism, just weeks after the cases began to be detected.

Scientific questions remain about what component of the vaccines might be triggering the reaction, and who is at risk. But the syndrome is so similar to the rare heparin-related reactions that scientists have given the vaccine-triggered reaction a similar name, established a probable link and identified a widely available diagnostic test. It’s clear that heparin shouldn’t be given because it may worsen the clots, but other treatments exist on the shelves of virtually any hospital, although they cannot undo the damage caused by severe clots.

In a letter Friday, scientists from Johnson & Johnson said that “evidence is insufficient to establish a causal relationship” between their shot and the clots, and called for more evidence to clarify the symptoms observed in people who had been vaccinated. But many experts, including U.S. government health officials, said the immune explanation is the leading theory.

On Monday, Rochelle Walensky, director of the Centers for Disease Control and Prevention, said health officials were examining “a handful” of additional cases to judge if they were the same rare reaction. Understanding the frequency of the events will help inform decision-making about how the vaccine should be used.

“I’m encouraged that it hasn’t been an overwhelming number of cases,” Walenksy said.

The rapid progress in understanding the clots highlights the dividends yielded by scientific research on seemingly narrow topics — and stands in stark contrast to the plight of other vaccines, in which scientists can struggle for years to understand why an adverse event occurs.

“It’s actually extraordinary we know so much about this already,” said Theodore Warkentin, a professor in the department of pathology and molecular medicine at McMaster University in Canada, who is one of the world’s experts on the heparin-triggered syndrome.

“Imagine if heparin had never been invented, but otherwise the world was the same. People would be getting these low platelets and clotting, and we wouldn’t even know where to start. … There was a road map.”

‘Pale, soft, salmon-colored clots’

For years, a relatively small circle of physicians and scientists have single-mindedly focused on unraveling the science behind a rare reaction to heparin that can cause both clotting and low platelet counts.

In 1957, two physicians from Dartmouth College’s medical school presented 10 cases of patients who had received heparin and developed unusual clotting reactions during a three-year period. The report, at a New York medical meeting, included photographs of the clots that had been removed, which were described as “pale, soft, salmon-colored clots,” according to a history Warkentin recounted in a textbook. The specialists in the audience were unconvinced, and none raised their hands when asked if they had seen similar cases.

During the next decades, recognition grew that rare reactions to heparin were real and that they were probably triggered by the immune system. A 1977 study detailing the cases of eight patients, six of whom were women, was considered key in establishing heparin-induced thrombocytopenia — known as HIT — as a recognized condition. A vascular surgeon in Milwaukee coined the term “white clot syndrome.”

Scientists would continue to learn more about HIT, discovering that a protein found inside platelets that also coated the surface of arteries and veins, called platelet factor 4, could bind strongly to heparin, forming a two-part complex.

In some people, when heparin and the protein bonded, the body’s disease-fighting system went on alert, triggering antibodies against platelet factor 4. That could wreak havoc. The antibodies could activate platelets, but with seemingly contradictory consequences: Some platelets would clot, while others would vanish. The antibodies could damage the cells lining blood vessels, helping trigger clots in more ways than one.

Because those antibodies could be detected in laboratory tests, physicians had an indispensable tool to diagnose the condition. The first iteration of a test was created by Warkentin’s mentor, John Kelton, in 1984.

It has taken years to work out the science of what is going on in HIT, and it remains an ongoing project. Scientists painstakingly developed mouse models that allowed them to study the condition and made a lab-generated monoclonal antibody that mimicked the one in the body. Warkentin and colleagues discovered a mysterious form of the condition that could occur, even in the absence of heparin.

“It’s funny, because you work in these areas and everyone in your family thinks it’s so esoteric and then something like this happens,” said Mortimer Poncz, division chief of pediatric hematology at Children’s Hospital of Philadelphia. “On the other hand, every time there is an unusual clot, someone is testing it for HIT these days. So it is simply exciting that turned out to be useful.”

An unusual type of clot

When something bad happens to a person after receiving a vaccine, the first question most scientists consider is whether it is related to the shot or simply a coincidence.

In the case of the brain blood clots identified in people in Europe who recently received the AstraZeneca vaccine, early inquiries focused on whether it was happening more frequently than the typical rate of such clots in the general population.

The brain blood clots, called cerebral venous sinus thrombosis, are rare — with about two to 14 cases expected in a population of 1 million people each year. The clots in recently vaccinated people were clearly more common than would be normal, occurring in a matter of weeks after healthy, young people received shots.

So far, 222 clots in the brain or abdomen have been identified out of 34 million people vaccinated in Europe — in far less than a year. But what stood out to physicians was that the ensemble of symptoms surrounding these clots was so atypical there wasn’t even an easy way to look up the rate of how often they would normally occur.

“People get blood clots. Those things happen,” said Steven Coutre, a hematologist at Stanford University Medical Center. “It’s one thing to have a blood clot; it’s another to have disseminated blood clots in an otherwise healthy woman who dies from it. That gets your attention.”

On a Friday in early March, Sabine Eichinger, a physician in Austria involved in the care of the first patient, a 49-year-old health-care worker, told Andreas Greinacher, an expert in Germany on HIT, about the unusual case. She agreed to send him a sample, and by the following Tuesday, Greinacher was talking with Warkentin about the parallels between the cases and the rare immune reaction to heparin, about which they had co-authored a medical textbook.

By the next day, Greinacher and colleagues had determined that a diagnostic test for the same antibodies implicated in HIT could be useful. Their paper was published alongside a report from Norwegian specialists, and proposed a new name for the syndrome: vaccine-induced immune thrombotic thrombocytopenia, or VITT. They suggested a possible treatment course, including intravenous immunoglobulin and other anticoagulants.

In the heparin-triggered condition, the culprit was the combination of heparin and platelet factor 4. In the vaccine cases, it appeared that something in the vaccine — what, exactly, is still under intense investigation — bound to platelet factor 4 and triggered a similar response.

“Just as an occasional patient zings off one of these huge responses after being given heparin and gets in trouble, the occasional person given these vaccines loses the regulatory control that keeps this immune response and zings off one of these high-titer antibody responses,” said Richard Aster, a senior investigator emeritus at Versiti, a nonprofit focused on blood health and research.

In five of the six U.S. patients who developed clots after receiving the Johnson & Johnson vaccine, physicians performed tests and found those same HIT antibodies. A 25-year-old man who received the vaccine in the clinical trial of the vaccine and suffered a brain clot also had HIT antibodies. The existence of those tests — and the ability to treat the condition — is a tribute to the years of experience studying HIT.

Paul A. Offit, a vaccine expert at Children’s Hospital of Philadelphia who developed a rotavirus vaccine, said the swift revelations about the mechanism of the blood clots in people receiving coronavirus vaccines stand in marked contrast to the experience trying to understand rare events associated with other vaccines. A vaccine for rotavirus, RotaShield, was pulled off the market in 1999 because it was found to carry a rare risk of intussusception, a condition that can cause intestinal blockage and may be deadly.

“It’s amazing, having lived through the intussusception experience,” Offit said. “That was 20-plus years ago, and we still don’t know the reason.”

But even as the science behind the clots is untangled, the parallel public health question of what to do with an effective vaccine with a rare risk remains.

Many have pointed out that the risk remains lower than the risk of clots from birth control or from a serious case of covid-19. But the clots are serious and can be devastating to individuals, and some groups appear to be at higher risk for the rare reaction. The Nebraska patient was initially treated with heparin, but was switched to a regimen recommended for patients with the rare vaccine reactions, according to a case study. She was critically ill as of Wednesday, when the report was published.

A panel of expert advisers to the Centers for Disease Control and Prevention is scheduled to debate the matter again Friday. European countries have, for the most part, restarted use of the AstraZeneca vaccine, often restricting it to older people for whom the benefits clearly outweigh the risks.

“We’ll never have perfect data, and there will always be uncertainty,” Grace Lee, a professor of pediatrics at Stanford University School of Medicine, said as the CDC committee debated how to move forward Wednesday. “But it’s really for me about getting better risk estimates … if we can, to minimize exposure to those who may be at highest risk for this particular adverse event.”