VITT Pathophysiology: An Update

Vaccine-induced thrombotic thrombocytopenia (VITT) is a rare thrombotic disorder first identified in 2021 as a catastrophic syndrome associated with anti-SARS-CoV-2 adenoviral vector (AdV)-vaccine administration. It is characterized by the presence of oligo- or monoclonal anti-PF4 antibodies able to induce in vitro platelet activation in the presence of PF4. In addition to this immune-based pathomechanism, random splicing events of the Adv-vector DNA encoding for SARS-CoV-2 spike protein resulting in the secretion of soluble spike variants have been postulated as a possible pathophysiological mechanism. More recently, some novel clinical-pathological anti-PF4-associated entities also characterized by thrombosis, thrombocytopenia, and VITT-like antibodies but independent from heparin or AdV-vaccine administration have been identified. To date, these VITT-like disorders have been reported following the administration of vaccines different from anti-SARS-CoV-2 AdV-vaccines, like human papillomavirus (HPV) and mRNA-based COVID-19 vaccines, following a bacterial or viral respiratory infection, and in patients with a monoclonal gammopathy of undetermined significance. The purpose of this review is to provide an update on the knowledge on VITT pathogenesis, focusing on recent findings on anti-PF4 antibodies, on a possible genetic predisposition to VITT, on VITT-antibody intracellular activated pathways, on lipid metabolism alterations, and on new VITT-like disorders.