This chain reaction could explain rare blood clots linked to some COVID-19 vaccines

illustration of a b cell surrounded by antibodies
B cell surrounded by antibodies (Image credit: Getty/CHRISTOPH BURGSTEDT/SCIENCE PHOTO LIBRARY)

A research group in Germany has presented a possible explanation for why the AstraZeneca and Johnson & Johnson COVID-19 vaccines sometimes trigger rare blood-clotting events. But not all experts are convinced the explanation is correct.

The group, led by Dr. Andreas Greinacher, head of the Institute of Immunology and Transfusion Medicine at University Hospital Greifswald, suggests a chain reaction that involves a preservative and certain proteins in the vaccines may be responsible for the rare blood clots. 

The team has completed relevant studies only on the AstraZeneca vaccine and recently began examining the Johnson & Johnson vaccine, The Wall Street Journal reported. However, Greinacher said he suspects that the mechanism that causes the rare blood clots may be common to both shots, as both vaccines use modified adenoviruses as their means of getting the vaccine into the body's cells, WebMD reported in April.

Related: AstraZeneca COVID-19 vaccine causes very rare blood clots, EU regulator says 

"My assumption is, and that's a hypothesis, that this is a class effect of vaccines using adenovirus," Greinacher told reporters during a call on April 20, WebMD reported. 

Adenoviruses are a family of viruses that typically trigger symptoms of the common cold in humans, but for use in vaccines, scientists modify the viruses so they cannot infect cells, Live Science previously reported. Instead, the viruses simply act as vessels to carry vaccine ingredients into the body. (The Johnson & Johnson vaccine uses a human adenovirus called Ad26, while the AstraZeneca shot contains an adenovirus that naturally infects chimpanzees.)

In addition to the AstraZeneca and Johnson & Johnson shots, the COVID-19 vaccines made by CanSino Biologics in China and the Russian Ministry of Health's Gamaleya Research Institute contain modified adenoviruses, Live Science previously reported. However, the latter two vaccines have not been linked to any unusual blood clotting events, the Journal reported. 

And it's important to note that, even with the former two vaccines, the observed clotting events are quite rare: In the U.K., for example, 168 cases of blood clots had been reported by April 14 in connection to the AstraZeneca vaccine, after more than 21.2 million doses had already been administered there, according to Cosmos. And as of Wednesday (May 12), the U.S. had reported 28 cases of rare clotting disorders linked to the Johnson & Johnson vaccine, out of more than 9 million total doses administered, The New York Times reported.

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"COVID-19 is much, much, much more dangerous than this extremely rare condition," Greinacher told the Journal.

That said, "understanding the cause [of the clots] is of highest importance for the next-generation vaccines, because [the novel] coronavirus will stay with us and vaccination will likely become seasonal," Dr. Eric van Gorp, a professor at Erasmus University in the Netherlands who heads a group of scientists studying the clots, told the Journal.

How the shots might cause clots 

Greinacher's group hypothesizes that, in rare instances, proteins in the vaccines set off a runaway immune response that quickly spreads throughout the whole body. In the AstraZeneca vaccine, the full-body response may emerge, in part, due to ethylenediaminetetraacetic acid (EDTA), a preservative in the shot and common stabilizer found in drugs.

During vaccine development, scientists grow the modified viruses in human cells; in their analyses, Greinacher's group identified more than 1,000 proteins in the AstraZeneca vaccine that are derived from these human cells, the Journal reported.

Once inside the body, the vaccine comes into contact with platelets, the small blood cells involved in clotting, the group concluded in a study posted April 20 to the preprint database Research Square. Exposure to the vaccine and its associated proteins "activates" the platelets, causing them to change shape and send out chemical signals to alert the immune system. The activated platelets also release a substance called platelet factor 4 (PF4), which normally helps modulate blood clotting in the body.

However, in some instances, PF4 latches onto components in the vaccine, likely some of the cell-derived proteins, and forms large "complexes" that the immune system mistakes as a threat, like an invasive bacterium. That causes immune cells to build new antibodies to attack PF4, triggering a violent immune response.

"Imagine this is like a dragon in the cave who was sleeping for a long time [but] which now got alerted by someone's throwing a stone on it," Greinacher said on the April call, according to WebMD.

Related: Quick guide: COVID-19 vaccines in use and how they work

With the "dragon" awake, EDTA enters. The preservative causes "leakage" in blood vessels near the injection site, at least in mice, the team found, and past studies also suggest that EDTA increases the permeability of blood vessels. Leaky blood vessels may release the PF4 complexes into the bloodstream and set off a body-wide reaction, the team hypothesized.

EDTA is not a listed ingredient in the Johnson & Johnson vaccine, but if the shot generates similarly large PF4 complexes, the basic mechanism behind the clotting may still be the same, Greinacher speculated, according to WebMD.

However, Greinacher is still working to confirm his theory. "[Greinacher's] hypothesis could be right, but it could also be wrong," Dr. John Kelton, a professor at McMaster University in Ontario who helps run Canada's reference lab for assessing patients with blood clots after vaccination, told The Wall Street Journal. Kelton and his colleagues were able to replicate some of Greinacher's findings but could not confirm the underlying cause of the blood clots.

Other research groups have suggested that the adenovirus shells that carry vaccines into the body may be a factor, as the family of viruses has been linked to blood clotting in the past, the Journal reported. Van Gorp's group has theorized that the clotting may stem from a spike in inflammation in the body following the shot. 

Still others have suggested that the shots may mess with the so-called complement system, a part of the immune system that helps to clear away pathogens and infected cells from the body, Science magazine reported. The spike protein — a structure that sticks off of the coronavirus — can bind to the lining of blood vessels and activate this complement system, and in some people, this may lead the complement system to attack the blood vessels themselves.

More research will be needed to know for sure. Read more at WebMD and The Wall Street Journal

Originally published on Live Science. 

Nicoletta Lanese
Channel Editor, Health

Nicoletta Lanese is the health channel editor at Live Science and was previously a news editor and staff writer at the site. She holds a graduate certificate in science communication from UC Santa Cruz and degrees in neuroscience and dance from the University of Florida. Her work has appeared in The Scientist, Science News, the Mercury News, Mongabay and Stanford Medicine Magazine, among other outlets. Based in NYC, she also remains heavily involved in dance and performs in local choreographers' work.