Potential role of heparin in the immune responses to PF4 and protamine. Heparin (red line) binds to PF4 and neutralizes cationic charge repulsion between tetramers, forming oligomeric complexes (shown here as a dimer for simplicity) that approximate anti-PF4/heparin (HIT antibody) binding sites (blue triangles). Close apposition of epitopes allows a single antibody to bind adjacent tetramers, thereby increasing antibody avidity (A). Heparin may also oligomerize protamine and approximate some immunogenic epitopes (blue squares) while obscuring others (yellow squares) from antibody binding (B). Panel A is adapted from Sachais et al, Blood. 2012; 120(5):1137-1142.¹⁰