Protein Interaction Causing Vaccine Related Thrombosis

Scientists from the University of Birmingham were able to identify how deadly blood clots occur due to protein interactions in the disease known as Vaccine-Induced Immune Thrombocytopenia and Thrombosis (VITT) in a recent paper published in Blood, thanks to funding from the National Institute for Health and Care Research and the British Heart Foundation. Previous research has revealed that patients with VITT develop antibodies that bind to a protein called Platelet factor 4 (PF4), resulting in the formation of a huge cluster of molecules known as an immunological complex. Following the formation of a complex, platelets and immune system cells cause clotting and inflammation, but the precise nature of what PF4 performs in this event was unknown.

In this latest investigation, the researchers used blood from healthy donors as well as serum and plasma from VITT patients to uncover for the first time how PF4 was directly implicated in platelet activation and thrombotic events. PF4 induced the formation of tiny cells known to cause clotting by adhering to a receptor called c-Mpl on the surface of platelets.

The major advances seen in vaccine development during the global Covid-19 pandemic were thrown into sharp relief following the tragic, rare cases of vaccine-induced immune thrombosis. While there were alternative vaccines available to continue to provide protection against the coronavirus in some countries around the world, understanding the mechanisms behind these cases are critical to ensuring that the technology for delivering vaccines can be used with confidence in the future.” – Dr Pip Nicolson, the University of Birmingham.

Dr Richard Buka, Research Fellow in the Institute of Cardiovascular Sciences and co-lead author “As well as identifying a new way in which platelets are being activated in a potentially deadly manner in VITT, our research has also been able to find how this mechanism may lead to new drugs to protect against blood clots in VITT and blood clots in general.”

The study also discovered that variations on a medicine used to treat bone marrow malignancies could be created to prevent VITT patients from lethal clots.

The researchers employed ruxolitinib, a medicine used to treat some forms of blood cancer, to inhibit the receptor activated by PF4 after the vaccine-induced event. Despite the fact that the current formulation of the medicine is unsuitable for usage in VITT patients, the researchers discovered that inhibiting the route with ruxolitinib decreased platelet aggregation and suggests a potential future method of protecting patients against blood clots.

“This work helps us to understand more fundamental things about how blood clots form and may also be relevant in other related diseases that are more common.”- Dr Samantha Montague, University of Birmingham

Dr Samantha Montague, Research Fellow in the Institute of Cardiovascular Sciences at the University of Birmingham and co-lead author of the paper said: “It is gratifying that we have been able to identify a new, important biological mechanism through trying to thoroughly understand a new disease. This work helps us to understand more fundamental things about how blood clots form and may also be relevant in other related diseases that are more common.

“Our ongoing research funded by the British Heart Foundation is looking at how we can identify patients who may develop VITT, with a view that future vaccine programmes around the world can be delivered while understanding and managing the potential risk for those few at greatest risk.”

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