Blood clots tied to vaccines can also occur spontaneously, scientists find

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In February, 2021, as health authorities around the globe raced to blunt the COVID-19 pandemic, reports began to emerge of a rare but serious adverse effect associated with one of the first vaccines to reach the public.

That vaccine, manufactured by Britain–based pharmaceutical company AstraZeneca, was soon connected to dangerous blood clots in about one in 66,000 recipients – a rate too low for the effect to have turned up in clinical trials of the vaccine.

Fast forward four years and the vaccine has long since been discontinued, along with one produced by Johnson & Johnson that caused a similar problem.

Now the quest to understand how the vaccines triggered blood clots has led scientists to a surprising discovery: According to a new study, the same effect can occur spontaneously in some individuals who were never exposed to the vaccine or any other external cause. The result does not mean the vaccine-related blood clots were themselves spontaneous. But it has shed light on a complex and sometimes dangerous blood interaction that, in all probability, has been present in humans since time immemorial but gone unnoticed until recently.

“We never knew how to recognize it – we didn’t have the tools,” said Theodore (Ted) Warkentin, a hematologist and emeritus professor at McMaster University in Hamilton, who led the new work, published Wednesday in the New England Journal of Medicine.

Dr. Warkentin first became involved in studying the vaccine-related blood clots in the spring of 2021 when he and colleagues at McMaster and in Germany realized that the problem resembled a condition involving heparin, commonly used as a blood thinner.

Although heparin is typically given to prevent clotting, it can sometimes cause antibodies to bind to a small protein found in human blood known as platelet factor (PF4). The antibodies can attach to more than one PF4 protein at time, tangling up into larger complexes that can then turn into blood clots. The condition, called HITT for heparin-induced thrombocytopenia and thrombosis, is uncommon but well-documented in medical literature.

Dr. Warkentin was among those who saw similarities to HITT in the early reports of blood clots linked to the AstraZeneca vaccine. Studies of emerging cases eventually led to the designation of a related vaccine-induced syndrome dubbed VITT. McMaster subsequently became Canada’s reference lab for confirming occurrences of VITT, with 46 cases identified in total according to Ishac Nazy, co-director of McMaster’s Centre for Transfusion Research. Federal government figures last updated in July, 2021, state that six people died of VITT across the country.

The cause of VITT turned out to be very much like the heparin-induced disorder, but with antibodies that attached to the PF4 molecules at a different location. Those antibodies were of a rare type that formed only in some patients in response to the adenovirus that was used to transport the AstraZeneca and Johnson & Johnson vaccines into patients’ cells. (The mRNA vaccines produced by Pfizer and Moderna use a different transport mechanism so do not generate those antibodies in any recipients.)

Yet, the end of the COVID global health emergency did not put an end to the blood clots.

In 2023, Dr. Warkentin and colleagues reported two cases of blood clots initiated by natural infections of an adenovirus. These cases were unconnected to vaccination yet produced a VITT-like effect featuring the same problematic antibodies. This spurred further research, including into the possibility that other kinds of viruses may do something similar.

That remains an open question. What Dr. Warkentin said he didn’t expect was to see cases that looked like VITT but in which the blood clots occurred without a virus or a vaccine acting as a trigger. Instead, those cases arose on their own.

Dr. Warkentin said the clue that led him to this realization turned up in 2023 when, after giving a seminar, he was approached by a physician who told him about a case in which the patient had twice tested positive when screened for HITT yet did not respond to treatment. The patient ultimately died.

For Dr. Warkentin, it was the fact that the patient had two tests more than a year apart that seemed particularly odd. If heparin has triggered the clots initially – or a vaccine, or a virus – why would clots still be occurring one year later? This did not match the characteristics of HITT.

“It doesn’t matter whether you’re treated or not,” he said. “If you survive, it still goes away.”

He asked technologist Jo-Ann Sheppard to devise a test to distinguish samples of HITT from VITT. Sure enough, the case Dr. Warkentin learned about after the seminar was more like VITT.

Further investigation eventually showed what was happening. The patient’s immune system was generating too many copies of one kind of antibody. In some cases, such a situation might be a precursor to cancer. But in this case, it was causing a more immediate and fatal problem, because the antibody being repeatedly copied was one that stuck to PF4, just like VITT antibodies do.

Dr. Warkentin then realized the case was similar to one he had learned of from colleagues in New Zealand. This was also included in the study. Next, he reached out to colleagues in Europe and three more cases emerged in Germany, France and Spain. On its own, each would have remained a medical mystery. Now there was a common thread.

“It’s a technical tour de force,” said Steven McKenzie, a professor of medicine at Thomas Jefferson University in Philadelphia, and an expert in the field who was not involved in the McMaster team’s work. “It really helps us move forward because they explain what’s going on and they tell you how to look for it.”

Dr. McKenzie added that there are important clinical implications from the work because patients with the rare condition do not respond to conventional treatments for blood clots.

“These are things that all of us around the world who see patients with blood clots need to be aware of,” he said.