COVID vaccination: we now may know why some people developed blood clots

COVID vaccines saved millions of lives, but months into the rollout, a small number of people began developing dangerous blood clots in unusual parts of the body. These only happened after vaccines that used a modified adenovirus to deliver its payload – such as the AstraZeneca vaccine. Why these blood clots formed was a mystery – until now.

The condition was named vaccine-induced immune thrombocytopenia and thrombosis, or VITT. It happens when the immune system mistakenly attacks one of the body’s own proteins, called platelet factor 4.

Antibodies that recognise platelet factor 4 are actually part of normal immune responses, but in VITT the antibodies that develop are unusually sticky. They cling on to platelet factor 4, pulling together many molecules and forming large clusters of proteins called “immune complexes”, leading to dangerous blood clots.

Over the last few years, we have been working on the biology of VITT, primarily focusing on how these antibodies activate platelets. However, the way that vaccination triggers these antibodies to form was one of the main mysteries in this disease.

Now an international team of scientists in Australia, Canada and Germany has provided an answer. In an elegant set of experiments, they showed that virtually all patients with VITT share a distinctive pattern in their antibodies.

They studied 100 patients with VITT from around the world. By chance, two of these patients had donated blood in the past, meaning samples were taken before vaccination and stored in German blood service freezers. These samples turned out to be the key that unlocked the mystery.

The team were able to show that the antibodies involved in VITT begin as antibodies that recognise an adenoviral protein called protein VII. These antibodies probably came from the immune system’s memory of earlier adenovirus infections – which are common in childhood and cause mild cold-like symptoms.

During normal immune responses to infection and vaccination, tiny random genetic changes occur in cells that produce antibodies. This is normal and these changes help the immune system refine antibodies so they fight infections more effectively.

In all the patients with VITT, the researchers found the same change. By changing just one small part of the antibody, it suddenly gained the ability to bind platelet factor 4 very strongly.

Previous research by the same team had already shown that most patients with VITT carry a particular immune gene variant that shapes the structure of the antibodies they produce.

The new study helps explain why this matters. The mutation identified by the researchers only occurs in antibodies built on this genetic background, allowing them to grab onto platelet factor 4 extremely tightly.

This discovery helps explain why VITT is so rare. Two unlikely events must occur at the same time. First, a person must inherit the particular immune gene variant. Second, a rare mutation must occur in one of the antibody-producing cells responding to the adenovirus. Only when both events happen together does the immune system begin targeting platelet factor 4.

Why do we need to understand VITT?

You might wonder why this is still important. The pandemic is over and surely VITT is no longer seen?

But adenovirus-based vaccines remain an important tool. They are versatile, inexpensive and easy to deploy worldwide. When the next pandemic arrives, vaccines made using this approach could once again save millions of lives.

We also occasionally see patients with syndromes that look exactly like VITT but without any link to vaccination. These cases can sometimes be triggered by viral infections, including adenovirus and cytomegalovirus.

A similar process has also been implicated in people with recurring blood clots over many years, repeated miscarriages and stroke in a newborn baby caused by antibodies from the mother that target platelet factor 4.

Understanding exactly how VITT happens means scientists may now be able to modify future vaccines to avoid triggering this rare immune reaction.

Richard Buka received funding from AstraZeneca to conduct research in an area of medicine unrelated to VITT. He has done consulting work for Pfizer. He is the Chair of HaemSTAR, a UK-wide network of haematology resident doctors interested in malignant haematology. He has previously been supported by the British Heart Foundation and his current post is funded by the UK National Institute of Health and Care Research (NIHR).

Samantha Montague receives funding from the British Heart Foundation (BHF) and was previously funded by the National Institute for Health Research (NIHR) (NIHR135073). The views expressed are those of the author(s) and not necessarily those of the NIHR or the BHF.