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 (black line) binds to a circumferential band of cationic residues on the surface of each PF4 tetramer; 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. Epitope approximation increases the avidity of KKO through increased proximity to more than 1 binding site on PF4 (1A). Some KKO antibodies may bind to epitopes on neighboring tetramers stabilizing ULCs induced by heparin (1B). In contrast, heparin has no such effect or may partially inhibit exposure of the epitope recognized by RTO (2).