Major new analysis from the Thrombotic Thrombocytopenia Syndrome (TTS) Consortium has provided critical insights into the rare but serious condition known as vaccine-induced immune thrombotic thrombocytopenia (VITT).

The findings, published in the journal Efficacy and Mechanism Evaluation, confirm a higher risk of arterial and venous thrombosis after COVID-19 infection compared to vaccination.

The TTS consortium sought to understand the reasons why there were rare instances of blood clotting with low platelets in some people who received the adenoviral AstraZeneca and Janssen vaccines.

The consortium employed a comprehensive approach across five work-packages. This included designing cohort studies covering the entire English population and analyzing local linked regional datasets to detect TTS occurrences in real-time.

This synopsis of findings from research conducted across the consortium, published in NIHR’s Efficacy and Mechanism Evaluation journal, has found that while the overall risk of blood clots was higher after COVID-19 infection than after vaccination, there was an increased risk of thrombosis and low platelet counts following the first dose of the AZD1222 vaccine. Subsequent doses of the AZD1222 vaccine or any doses of mRNA-based vaccines did not show the same risk.

Other key findings include:

• The development of antibodies to a small protein released by platelets called Platelet Factor 4 (PF4), which is a key feature of VITT, was probably due to an interaction between the negatively charged “hexon” proteins in the adenoviral vaccine and the positively charged PF4.
• Antibodies to the PF4 protein are uncommon in healthy individuals, vaccinated individuals, and those infected with COVID-19. By contrast, the levels are very high in patients with VITT.
• Whole genome sequencing revealed no significant genetic variants predisposing individuals to VITT, though further RNA sequencing studies are ongoing.
• A strong immune response is seen in VITT patients—the formation of neutrophil extracellular traps (these are like sticky spider webs formed by white blood cells) and inflammatory reactions, collectively contributed to clot formation.

Chief Investigator of the TTS Consortium, the University of Liverpool’s Professor Sir Munir Pirmohamed, said, “This research provides important information for vaccine developers and health authorities worldwide. Our findings not only clarify the risk factors for TTS but also offer pathways for better patient management in the future.”

The consortium recommends the establishment of a national reference laboratory and registry to improve diagnosis and tracking of TTS cases. Additionally, the findings suggest that future adenoviral vector-based vaccines could be modified to reduce interactions with PF4 and minimize the risk of immune-related complications.

With implications for vaccine safety, public health policies, and the treatment of rare clotting disorders, this study marks a significant step forward in understanding TTS, including VITT. Understanding how TTS occurs with or without proximate vaccine exposure is important to facilitate diagnosis and rapid treatment, and prevent serious consequences from this rare syndrome.

“Unraveling the immune trigger behind VITT will give clinicians clear guidance to recognize and manage the rare—but increasingly reported—VITT-like clotting syndromes,” said Dr. Pip Nicolson, first author.

“These findings provide a springboard for developing faster diagnostic tools and, importantly, draw attention to the unmet challenge of the long-term symptom burden many VITT survivors still face—knowledge that will steer future research and help reassure the public that vaccination remains a safe and essential cornerstone of public health.”