Scientists have identified the biological mechanism behind a rare but serious blood-clotting condition linked to some early COVID-19 vaccines, shedding new light on a medical mystery that emerged during the global vaccination rollout in 2021.
The breakthrough follows years of investigation that began when hematologist Sabine Eichinger of the Medical University of Vienna encountered a troubling case shortly after the first COVID-19 vaccines were introduced across Europe.
A 49-year-old nurse developed unusual blood clots and uncontrollable bleeding after receiving the Oxford–AstraZeneca COVID‑19 vaccine. Despite medical intervention, the woman died, prompting Eichinger to search for answers.
“I could barely sleep,” she later recalled, adding that she even attended the patient’s autopsy in hopes that another explanation would emerge. When none did, she turned to German hematologist Andreas Greinacher of the University of Greifswald, who had spent decades studying similar clotting disorders linked to the blood thinner heparin.
Within days, Greinacher’s laboratory confirmed the presence of antibodies targeting platelet factor 4 (PF4)—a protein involved in blood clotting. This discovery helped identify a newly recognized condition known as Vaccine‑Induced Immune Thrombocytopenia and Thrombosis (VITT).
Soon afterward, similar cases were reported among people who had received the Johnson & Johnson COVID‑19 vaccine in the United States.
Although the syndrome proved extremely rare—occurring in roughly one out of every 200,000 vaccinated individuals—it raised safety concerns. Several European countries limited the use of the AstraZeneca vaccine to older adults or discontinued it entirely, while the Johnson & Johnson shot was eventually withdrawn from widespread use in the U.S.
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In a study published in The New England Journal of Medicine, scientists demonstrated how proteins from adenoviruses—used as delivery systems in certain vaccines—can trigger the production of harmful antibodies in rare cases.
Both the AstraZeneca and Johnson & Johnson vaccines used modified adenoviruses to deliver genetic instructions for the coronavirus spike protein into human cells. According to the study, in individuals with a particular genetic predisposition and specific mutations in antibody-producing B cells, the immune system mistakenly creates “rogue antibodies.”
Instead of attacking the viral spike protein, these antibodies bind to PF4, triggering a chain reaction that activates platelets and leads to dangerous blood clots while simultaneously depleting platelets needed to prevent bleeding.
“This is a beautiful piece of work,” said Stanley Plotkin, a veteran vaccine developer and professor emeritus at the University of Pennsylvania. Hematologist Gowthamai Arepally of Duke University described the findings as “groundbreaking.”
Immunologists Jing Jing Wang and Tom Gordon from Flinders University previously discovered that all VITT patients produced nearly identical antibodies targeting PF4. Meanwhile, hematologist Theodore Warkentin of McMaster University documented rare cases in which natural adenovirus infections caused similar symptoms.
Further analysis using mass spectrometry showed that antibodies from VITT patients shared a distinctive feature: a negatively charged amino acid at a specific position in the antibody structure. This unusual characteristic strengthened the antibody’s attraction to PF4, which carries a positive charge.
When these antibodies bind to PF4, they create clusters that activate platelets, triggering a cascade that forms blood clots while exhausting the body’s platelet supply—resulting in severe bleeding.
To confirm the mechanism, scientists recreated the antibodies in laboratory experiments. When injected into mice, the antibodies caused symptoms similar to VITT. However, when researchers corrected the mutation responsible for the negative charge, the antibodies bound weakly to PF4 and caused far fewer clots.
The study also identified the likely trigger of the abnormal immune response: an adenovirus protein known as protein VII (pVII). Scientists found that the rogue antibodies attach to a small segment of this protein that resembles a structural feature of PF4.
Researchers believe that prior exposure to adenoviruses may prime certain immune cells to recognize the protein. When vaccinated, those cells may undergo mutations that occasionally produce the harmful antibody variant responsible for VITT.
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According to the European Medicines Agency, about 900 VITT cases were reported in Europe following AstraZeneca or Johnson & Johnson vaccinations, including roughly 200 deaths. However, the AstraZeneca vaccine alone was administered more than three billion times globally and is estimated to have saved millions of lives.
The findings could help scientists improve the safety of future vaccines that use adenovirus technology. These vaccines are attractive because they are relatively inexpensive to produce and easier to distribute than mRNA vaccines since they do not require ultra-cold storage.
Adenovirus-based vaccines are already used in some Ebola immunization programs and are being developed to combat diseases such as influenza, malaria, meningitis, tuberculosis, and emerging threats like Nipah virus.
Vaccinologist Sarah Gilbert of the University of Oxford, who helped develop the AstraZeneca vaccine, said the discovery offers a clearer path to improving the technology.
“Adenoviral vectors have a major role to play in producing new vaccines against outbreak pathogens,” she said, noting that modifying viral proteins to reduce similarity with PF4 could potentially reduce the risk of VITT.
Researchers say more studies are needed, but the new findings represent a major step toward understanding—and preventing—one of the rare complications associated with early COVID-19 vaccination efforts.