Importance of PF4/heparin ultralarge complexes (ULCs) in HIT pathogenesis. (A) PF4, a positively charged protein, binds to negatively charged heparin through electrostatic interactions to form ULCs that govern HIT biology. At concentrations of PF4 or heparin excess, repulsive forces from excess charge predominate and are not permissive for complex formation. At stoichiometric ratios associated with charge neutralization, ULCs form capable of biological effects associated with in vivo immunogenicity³³  (B), differential clinical effects of UFH and LMWH³¹  (C), and heparin-dependent reactivity in laboratory assays¹⁹  (D).