Figure 1
Figure 1. Oligomerization of the HIT antigen. (A) PF4 and ULC formation and dissociation. PF4 tetramers exist in a dynamic equilibrium with dimers and monomers. Under normal circumstances, tetramerization is favored when PF4 is bound to cellular GAGs (right pointing arrow on left side of figure), leading to a high surface density of PF4 and a propensity to form oligomers that are capable of binding multiple HIT antibodies. Heparin promotes the formation of PF4 ULCs in solution and on cell surface GAGs, which clusters antibody as well. The addition of 2-O, 3-O desulfated heparin (ODSH) disrupts ULCs into smaller complexes that bind fewer antibodies (right side of figure). Similarly, PF4 antagonists impede PF4 tetramerization (upward pointing arrows on left side of figure), leading to a lower surface density of PF4 tetramers, less propensity to form ULCs, and fewer sites for antibody binding. (B) Schematic of pathogenic versus nonpathogenic antibody binding. Simplest model showing distinction between effects of heparin on binding of pathogenic (KKO) and nonpathogenic (RTO) anti-PF4 antibodies. Heparin (orange) binds to a circumferential band of cationic residues on the surface of each PF4 tetramer (blue); the interrupted line represents binding to the distal side of the tetramer. Heparin neutralizes cationic charge repulsion among PF4 tetramers forming oligomeric complexes (shown here as a dimer for simplicity), which approximates the binding sites for KKO (panel B 1A,1B). Epitope approximation increases the avidity of KKO through increased proximity to more than 1 binding site on PF4 (1B). Some KKO antibodies may bind to epitopes on neighboring tetramers stabilizing ULCs induced by heparin (1A). In contrast, heparin has no such effect or may partially inhibit exposure of the epitope recognized by RTO (2). (C) Disruption of PF4 tetramerization. Two PF4 dimers are shown as ribbon diagrams based on the published crystal structure. A PF4 antagonist (gray) is bound to the lower dimer (red/blue) preventing association with the upper dimer (purple/cyan).

Oligomerization of the HIT antigen. (A) PF4 and ULC formation and dissociation. PF4 tetramers exist in a dynamic equilibrium with dimers and monomers. Under normal circumstances, tetramerization is favored when PF4 is bound to cellular GAGs (right pointing arrow on left side of figure), leading to a high surface density of PF4 and a propensity to form oligomers that are capable of binding multiple HIT antibodies. Heparin promotes the formation of PF4 ULCs in solution and on cell surface GAGs, which clusters antibody as well. The addition of 2-O, 3-O desulfated heparin (ODSH) disrupts ULCs into smaller complexes that bind fewer antibodies (right side of figure). Similarly, PF4 antagonists impede PF4 tetramerization (upward pointing arrows on left side of figure), leading to a lower surface density of PF4 tetramers, less propensity to form ULCs, and fewer sites for antibody binding. (B) Schematic of pathogenic versus nonpathogenic antibody binding. Simplest model showing distinction between effects of heparin on binding of pathogenic (KKO) and nonpathogenic (RTO) anti-PF4 antibodies. Heparin (orange) binds to a circumferential band of cationic residues on the surface of each PF4 tetramer (blue); the interrupted line represents binding to the distal side of the tetramer. Heparin neutralizes cationic charge repulsion among PF4 tetramers forming oligomeric complexes (shown here as a dimer for simplicity), which approximates the binding sites for KKO (panel B 1A,1B). Epitope approximation increases the avidity of KKO through increased proximity to more than 1 binding site on PF4 (1B). Some KKO antibodies may bind to epitopes on neighboring tetramers stabilizing ULCs induced by heparin (1A). In contrast, heparin has no such effect or may partially inhibit exposure of the epitope recognized by RTO (2). (C) Disruption of PF4 tetramerization. Two PF4 dimers are shown as ribbon diagrams based on the published crystal structure. A PF4 antagonist (gray) is bound to the lower dimer (red/blue) preventing association with the upper dimer (purple/cyan).

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