Heparin-PF4 antibodies can cross-react with NA-PF4 and induce platelet activation. IgG heparin-PF4 antibodies react with heparin-PF4 complex or NA-PF4 complex, the antigen-IgG complex then binds to and cross-links platelet FcγRIIA receptors resulting in platelet activation with granule and microparticle release, platelet aggregation, and thrombus formation. The light green square indicates PF4; the olive green inverted symbol represents the neo-epitope that emerges after PF4 undergoes a conformational change after heparin or nucleic acid binds PF4; and the magenta symbol indicates that the heparin-PF4 IgG antibody cross-reacts with nucleic acid-PF4.