A study published has revealed for the first time the mechanism responsible for blood clot arising from thrombosis with thrombocytopenia syndrome (TTS) following vaccination with AstraZeneca vaccine.
A multi-institutional study published on December 1 in the journal Science Advances has revealed for the first time the mechanism responsible for blood clot arising from thrombosis with thrombocytopenia syndrome (TTS) following vaccination with AstraZeneca vaccine. Thrombocytopenia syndrome causes low platelet count. A low number of platelets – blood cells that help prevent blood loss when vessels are damaged – can result in no symptoms or can lead to an increased risk of bleeding or, in some cases, clotting.
Thrombosis with thrombocytopenia syndrome is a very rare serious adverse effects following vaccination using chimpanzee adenovirus Y25 (ChAdOx1), human adenovirus type 26 (HAdV-D26), and human adenovirus type 5 (HAdV-C5).
In June 2021, scientists from Germany and Norway reported that antibodies that activated the platelets, a blood component involved in clotting, were seen in young people who developed the clots after vaccination with AstraZeneca vaccine. But the precise mechanism behind it was not known then.
AstraZeneca vaccine and the Indian counterpart Covishield use the chimpanzee adenovirus Y25, while Johnson & Johnson vaccine uses the human adenovirus type 26. The Sputnik vaccine uses both human adenovirus type 26 and human adenovirus type 5 as vectors to ferry the spike protein into certain cells.
The researchers found that all three adenoviruses used in a few COVID-19 vaccines as vectors bind to platelet factor 4 (PF4). They found that adenoviruses form stable complexes with PF4.
According to an Arizona University release, in very rare cases, the viral vector may enter the bloodstream and bind to PF4, where the immune system then views this complex as foreign. The scientists believe this misplaced immunity could result in the release of antibodies against PF4, which bind to and activate platelets, causing them to cluster together and triggering blood clots in a very small number of people after the vaccine is administered.
They used state-of-the-art computational simulations to demonstrate an electrostatic interaction mechanism between platelet factor 4 (PF4) and the viral vector used in the AstraZeneca vaccine. They determined the structure of the viral vector used in AstraZeneca vaccine to carry out the computational simulation. In addition, the researchers also confirmed it through in vitro studies involving cell-based experiments and surface plasmon resonance.
“Vaccine-induced immune thrombotic thrombocytopenia (VITT) only happens in extremely rare cases because a chain of complex events needs to take place to trigger this ultra-rare side effect. Our data confirms PF4 (platelet factor 4) can bind to adenoviruses, an important step in unravelling the mechanism underlying VITT. Establishing a mechanism could help to prevent and treat this disorder,” Dr. Alan Parker, an expert in the use of adenoviruses for medical applications from Cardiff University’s School of Medicine, said in the release.
“We hope our findings can be used to better understand the rare side effects of these new vaccines – and potentially to design new and improved vaccines to turn the tide on this global pandemic,” he added.
The scientists believe that the specific interaction between the fibre knob protein of the adenovirus and platelet factor 4 (PF4), and the manner the complex is presented to the immune system might prompt the immune system to see it as foreign and release of antibodies against this complex.
One of the ways the fibre knob protein of the adenovirus and platelet factor 4 tightly bind is through electrostatic interactions. The group showed that the fibre knob protein is mostly electronegative across approximately 90% of its surface, interrupted in interhexon spaces, where the surface potential rises. On the other hand, the platelet factor 4 (PF4) has a strong electropositive surface potential. This makes the fibre knob protein attract other positively charged molecules, particularly the platelet factor 4 (PF4) to its surface.
They found that the human adenovirus type 26 (HAdV-D26) has an overall electronegative surface potential but less strong than chimpanzee adenovirus used in AstraZeneca vaccine.
“We demonstrate that this interaction is not specific to chimpanzee adenovirus Y25 (ChAdOx1) fibre knob protein and that platelet factor 4 forms interactions with Ad5 and Ad26 with similar affinity. We also observed that heparin reduces the ability of platelet factor 4 (PF4) to associate with chimpanzee adenovirus fibre knob protein,” they write.
The human adenovirus type 26 has also been implicated in TTS at a similar frequency to chimpanzee adenovirus Y25 (ChAdOx1) on a per dose basis. Using a previously published model of Ad26, the researchers performed simulations for ChAdOx1 and observed that platelet factor 4 (PF4) contacted Ad26 less frequently than ChAdOx1. But further studies are needed with Ad26 before reaching any conclusions, they note.
“Current clinical guidance from the World Health Organization advises against the use of heparin in the treatment of TTS. Although our data suggest that heparin may inhibit the proposed interaction between ChAdOx1 and PF4, it does not provide any insights as to the effect of heparin on patients after they develop symptoms or its behaviour in the wider biological context. Therefore, it is important to continue to adhere to current clinical guidance pending further studies on the role of heparin in TTS,” they write.
“With a better understanding of the mechanism by which PF4 and adenoviruses interact there is an opportunity to engineer the shell of the vaccine, the capsid, to prevent this interaction with PF4. Modifying ChAdOx1 to reduce the negative charge may reduce the chance of causing thrombosis with thrombocytopenia syndrome,” Dr. Alexander T. Baker from Arizona University says in the release.