Progression of VITT: current evidence and proposed models. (a) After vaccination, vaccine components can enter the intravascular space via two routes. The first route is by accidental intravascular administration. The second route is mediated by the presence of EDTA in the vaccine composition that chelates calcium from cell–cell junctions and acts as proinflammatory trigger by enhancing vascular permeabilization. Within the first two days after vaccination with adenoviral vectors, neoepitope is generated on PF4 after interaction with viral hexons or so far unidentified vaccine constituent. The photomicrographs depicting the interaction of viral hexons with platelets and PF4 are based on [16]. (b) Within immunization time, marginal zone B-cells recognize neoepitope on PF4 and secrete non-pathogenic as well as pathogenic anti-PF4 antibodies, high avidity pathogenic anti-PF4 antibodies and anti-platelet PF4-independent antibodies carried into the bloodstream. (c) Within 5–20 days after vaccination, thrombosis and thrombocytopenia are manifested. Pathogenic anti-PF4 antibodies as well as high avidity pathogenic anti-PF4 antibodies result in FcγIIa receptor-mediated platelet activation, NETosis and to a minor extent also extracellular trap formation by monocytes, consequently enabling thrombus formation. Thrombus propagation is additionally favored by interactions of PF4 with von Willebrand Factor and monocytes with complement component 1r (C1r) expressed on endothelial cells. Monocyte–platelet aggregates accentuate thrombosis by expression of tissue factor (TF) (upper panel). Anti-platelet PF4-independent antibodies bind to glycoproteins on platelets, and a hypothesis was put forth [75] that this binding facilitates opsonization of platelets and subsequent clearing by phagocytosis, resulting in exacerbated thrombocytopenia in some cases of VITT (lower panel).