Current concept of the pathogenesis of VITT. The schematic presentation shown in A is speculative and in large part inferred from experiments in HIT. The schematic presentation of the downstream prothrombotic process shown in Panel B is largely substantiated by experimental data, some performed with VITT antibodies, others with HIT antibodies. Modified from Greinacher et al.45 (A) After vaccination, PF4 comes in contact with vaccine constituents and activates B-cells. Left side: It has been proposed that a direct inadvertent breach in the microvasculature at the vaccination site by IV injection or by disruption of vascular endothelial-cadherin tight junctions by EDTA in ChAdOx1, allows vaccine constituents to enter the circulation.45 Within the circulation, adenovirus particles can bind to platelets and can also bind PF4 released by activated platelets or from the matrix coating the microvascular endothelium.46,47 Platelets may become activated by vessel injury caused by injection of vaccine, after binding of the virions to the cell surface, or by immune complexes formed between contaminating host cell-line proteins in the vaccine and natural IgG antibodies against these proteins. Whether the virions themselves or another yet unknown constituent in the vaccine causes a conformational change in PF4 is unknown. Middle: once complexes with PF4 have formed, natural IgM antibodies activate complement (as it has been shown for PF4/heparin complexes),48 which enhances their proximity to B-cell receptors. In a mouse model, IV injection of ChAdOx-1, platelet-bound adenoviral particles are transported to the marginal zone of the spleen where B-cells are activated upon direct contact.49 However, electron microscopy and super resolution microscopy revealed complexes between PF4 and anti-PF4 VITT antibodies with amorphous constituents of the vaccine rather than virus particles.50 Beside the virions, other potential partners for PF4 include unassembled hexons51 and host cell-line proteins, although there is little overlap in the proteins contaminating ChAdOx1 and Ad26.COV2 vaccines.51 Right side: eventually, complexes of PF4 and vaccine (constituents) come in contact with B-cells expressing a cognate Ig receptors for PF4, either as fluid phase complexes, as virion-PF4 complexes, or the complexes are presented by platelets. (B) From right to left. After clonal expansion and isotype switching of one or a few B-cell clones, high titer IgG anti-PF4 antibodies are released into the circulation.52,53 Immune complexes containing PF4 and anti-PF4 IgG cluster and signal through FcRγIIA,50,54 which generates procoagulant platelets, induces platelet/neutrophil aggregates,55 and stimulates NETosis by neutrophils.50,54,56 DNA released by NETosis amplifies immune injury and activates complement, which deposits on the endothelium.57,58 Endothelial cells become activated, expressing tissue factor and releasing von Willebrand factor (VWF). VWF binds PF4 and subsequently anti-PF4 antibodies, which in turn further activates neutrophils and further propagates thrombin generation.59 Professional illustration by Patrick Lane, ScEYEnce Studios.
