A schematic representation of the interaction HIT-IgG with platelets. In panel A platelet factor 4 (PF4) is released from platelet α-granules after platelet activation. The PF4 binds to the platelet surface through glycosaminoglycans (GAGs) that are associated with tetramers of PF4. Panel B shows heparin binding to the PF4. The size of the PF4 bundle in part is related to the chain length of the heparin. Panel C shows HIT-IgG binding to epitopes on the PF4/heparin complex. Panel D shows ultra-large complexes (ULC) of heparin/PF4 and IgG binding to platelets via the platelet FcRγIIa. The immune complexes are potent platelet activators leading to the release of platelet-derived procoagulant microparticles.