Researchers from the University of Birmingham shared in October 2023 that a paper in Blood identifies how blood clots associated with Vaccine-Induced Immune Thrombocytopenia and Thrombosis (VITT) occur. Building on previous studies that have highlighted that patients with VITT produce antibodies that bind to Platelet factor 4 (PF4), the team used blood donated by healthy participants and serum and plasma from patients with VITT to understand the role of PF4.
Platelet factor 4 (PF4), known also as C-X-C motif ligand 4 (CXCL4) is a 7.8 kDa chemokine released from platelet α-granules. It forms “tetramers with a compact globalar structure” and a “strong equatorial positive charge”. Furthermore, it binds strongly to negatively charged molecules such as endothelial proteoglycans and “infectious agents”.
Although antibodies to PF4 “underlie the pathogenesis” of both heparin-induced thrombocytopenia (HIT) and VITT, the “direct effect of PF4 on platelets has not been extensively studied”. In the recent study, the authors demonstrate that PF4 binds the thrombopoietin (TPO) receptor, c-MPL, causing activation of Janus kinase 2 (JAK2).
A confident future
Dr Phillip (Pip) Nicolson suggests that the “major advances” in vaccine development prompted by the COVID-19 pandemic were “thrown into sharp relief” after the identification of “rare cases” of VITT.
“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 Richard Buka commented that the team not only identified a “new way” the platelets are being activated but have paved the way for “new drugs to protect against blood clots”. The research indicated that ruxolitinib, a treatment for some types of blood cancer, can block the receptor being triggered by PF4. However, in its current form it is “unsuitable for use in VITT patients”. Despite this, the identification of this pathway demonstrates a “potential future way to protect patients”.
Dr Samantha Montague stated that it is “gratifying” to have identified 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.”
Funded by the British Heart Foundation, the team will continue to explore how patients at risk of VITT can be identified to improve vaccine deployment.
“Future vaccine programmes around the world can be delivered while understanding and managing the potential risk for those few at greatest risk.”