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Members of the McMaster University researcher team that helped to explain the mechanism behind COVID-19 vaccine induced blood clots including doctors Ishac Nazy, left, Angela Huynh, John Kelton, Donald Arnold and Mercy Daka.JAMES W SMITH/James Smith

Canadian researchers have established the most definitive link yet between the Oxford-AstraZeneca COVID-19 vaccine and a rare blood clotting syndrome that shattered public confidence in the vaccine earlier this year.

The work, conducted by a team at McMaster University, has yielded a more efficient way to test for the syndrome and also lays out the underlying mechanism that is producing blood clots in a small fraction of vaccinated individuals. Investigators say their study, published Wednesday in the journal Nature, could also help speed efforts to identify which ingredient – or combination of ingredients – in the vaccine may be responsible for triggering the blood clots.

And while Canada has shifted away from the AstraZeneca vaccine, the study is relevant for other countries who have limited access to costlier alternatives and urgently need to protect their populations from the pandemic.

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“The vaccine is still going to be used for a while,” said John Kelton, co-medical director of McMaster’s Platelet Immunology Laboratory. “Part of what we’re doing is asking exactly how the blood clots happen,” and whether they can be avoided, he added.

The Hamilton facility has been the country’s reference laboratory for the blood-clotting condition known as vaccine-induced immune thrombotic thrombocytopenia, or VITT, since the first cases began emerging in Canada in April.

By then, it was known that the condition bears striking similarities to one that can sometimes arise when patients receive the blood-thinning drug heparin. In that situation, heparin can link up with a clotting factor in the blood stream called PF4. This ultimately causes blood platelets to aggregate and form clots.

Patients who develop VITT appear to have a corresponding set of antibodies that initiate the clotting much the way that heparin does. These are distinct from the antibodies that are produced to combat the virus that causes COVID-19.

In their study, the McMaster researchers used blood samples obtained from five Canadian patients with VITT. They compared the samples with blood from patients who had clots induced by heparin, and to samples from healthy patients.

They found the antibody response in the VITT patients was distinct in ways that allowed them to tell the difference between these and the heparin related cases.

The finding is significant because it should enable manufacturers to modify widely available commercial tests in order to allow for faster confirmation of VITT at hospitals and regional centres around the world, said Ishac Nazy, the lab’s scientific director and senior author on the study.

“It takes time to ship samples to a lab like ours for testing,” Dr. Nazy said. “This is a problem because the timing of a [VITT] diagnosis is very important for treatment.”

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According to figures posted by the Public Health Agency of Canada, just less than 1.6 million people across the country have received the AstraZeneca vaccine or its India-made counterpart Covishield. As of June 25, there have been 55 occurrences of blood clots linked to those vaccines, including six deaths. A total of 38 of those were tested and found to have the tell-tale indicators of VITT in their blood.

Four additional reports of blood clotting have arisen in individuals who received an mRNA vaccine made by Pfizer-BioNtech or Moderna, but researchers have not been able to determine whether those incidents are related to vaccination or other health issues. More than 22 million Canadians have now received at least one dose of an mRNA vaccine.

The National Advisory Committee on Immunization has designated mRNA vaccines as the preferred option when available and recommends Canadians who received a first dose of AstraZeneca take an mRNA vaccine as a second dose.

The McMaster team set out to show how the VITT antibodies behave in the presence of PF4. To do this, they used a series of mutated versions of the clotting factor they had previously developed and which helped narrow down which part of the PF4 molecule is important to the antibodies.

They found the antibodies attach to PF4 at the same location that heparin does but more strongly. The antibodies also link up with each other to create large networks, “like bunches of grapes,” that move through the blood stream, activating platelets and stimulating the release of still more PF4 in a cascade effect that soon leads to clotting, Dr. Kelton said.

One thing that remains unclear is the difference between the vast majority of individuals who receive the vaccine and suffer no ill effects, and the handful who develop VITT antibodies in large enough numbers to start the cascade.

“It appears that VITT is like a perfect storm – where a specific exposure in a specific person can lead to a specific antibody that can cause clotting,” said Donald Arnold, the lab’s other medical co-director.

Andreas Greinacher, a clinical researcher at the University of Greifswald in Germany who first drew public attention to the similarity between vaccine-related blood clots and the heparin-induced condition, said the Canadian study explains the interaction of the VITT antibodies and PF4, but he added there is evidence that in some patients other factors are also playing a role.

“An open question is why these antibodies are formed after vaccination,” he added.

Dr. Kelton said the McMaster group is now looking at how to narrow the search for which component of the AstraZeneca vaccine – and to a lesser extent the Johnson & Johnson vaccine, which is also connected with VITT but with a lower frequency – may be acting as a trigger that causes some people to produce VITT antibodies.

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