Abstract
Several recent reports have highlighted the onset of vaccine-induced thrombotic thrombocytopaenia (VITT) in some recipients (approximately 1 case out of 100k exposures) of the ChAdOx1 nCoV-19 vaccine (AstraZeneca). Although the underlying events leading to this blood-clotting phenomenon has yet to be elucidated, several critical observations present a compelling potential mechanism. Thrombus formation requires the von Willebrand (VWF) protein to be in ultra-large multimeric state. The conservation of this state is controlled by the ADAMTS13 enzyme, whose proteolytic activity reduces the size of VWF multimers, keeping blood clotting at bay. However, ADAMTS13 cannot act on VWF that is bound to platelet factor 4 (PF4). As such, it is of particular interest to note that a common feature between subjects presenting with VITT is high titres of antibodies against PF4. This raises the possibility that these antibodies preserve the stability of ultra-large VWF complexes, leading to the formation of endothelium-anchored VWF strings, which are capable of recruiting circulating platelets and causing uncontrolled thrombosis in terminal capillaries. Here, we share our viewpoint about the current understanding of the VITT pathogenesis involving the prevention of ADAMTS13’s activity on VWF by PF4 antibody-mediated stabilisation/ protection of the PF4-VWF complex.
Highlights
We summarized the recent understanding about ADAMTS13 and provided our viewpoint on the potential impact of ADAMTS13 on vaccine-induced thrombotic thrombocytopenia (VITT)
There is no doubt that platelet factor 4 (PF4) is a crucial contributor in the regulation of the proteolysis of von Willebrand factor (VWF) via ADAMTS13 and could play a role in the protection of VWF from proteolysis at the site of plug formation, too
The vaccine injection containing the adenovirus could cause micro-bleeding and the autoimmune effect. It is still elusive which component of the anti SARS-CoV-2 vaccine is involved in the process of forming antibodies against PF4
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. We will present how the autoantibodies against PF4 could mimic heparin by binding to PF4 and forming clusters with platelets As a consequence, these complexes with platelet factor PF4 are promoting the persistence of endothelium-anchored ultra-large VWF strings which are capable of recruiting circulating platelets and causing uncontrolled thrombosis in terminal capillaries, by promoting aggregation, platelet consumption, and micro-thrombi formation within the capillary network (e.g., cerebral and/or splanchnic vein thromboses). Johnston et al showed already in their report that PF4 was able to bind at multiple sites on VWF strings, and that the in vitro supplementation with ADAMTS13 was insufficient to prevent the forming of the earlier mentioned complexes [5] This notwithstanding, we present in this commentary piece, a new point of view on VITT that connects ADAMTS13, PF4, and VWF
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