Proposed model of PF4-dependent, heparin-independent HIT antibody-mediated platelet binding/activation. (A) According to a widely held model, HIT antibodies bind to complexes of PF4 and heparin formed on or near the platelet surface; IgG Fc domains clustered in this way cross-link platelet FcγRIIa, triggering platelet activation. Because all HIT antibodies bind to heparin/PF4 complexes, this model does not explain why only a subset of antibodies is platelet-activating or why thrombotic risk persists for several months in patients recovered from HIT. (B) An alternative model suggested by findings described here proposes that platelet-activating antibodies differ qualitatively from those that are nonactivating, in being able to recognize subtle conformational changes induced in PF4 when it binds to chondroitin sulfate (CS) normally displayed on the platelet membrane. Small quantities of PF4 may always be present on the platelet surface in a complex with CS and can be recognized by these antibodies. If bound IgG is clustered sufficiently, IgG Fc domains cross-link FcγRIIa, leading to platelet activation. Resulting release of PF4 could further increase levels of CS/PF4 on the platelet surface, leading to additional antibody binding and acceleration of the activation process.