Heparin-induced thrombocytopenia (HIT) is an important drug reaction that causes life- and limb-threatening thrombosis. It is considered a “clinical-pathologic” disorder, as the diagnosis is generally made by evaluating various “clinical” criteria (Thrombocytopenia, its Timing of onset, Thrombosis, and absence of oTher explanations, ie, the 4Ts scoring system) and determining whether (“pathologic”) HIT antibodies can be detected in the laboratory. Pathogenic heparin-induced antibodies are of the IgG class and activate platelets via their FcγIIA receptors (platelet IgG receptors), at concentrations of heparin ranging from 0 to 0.5 International Units/mL; characteristically, platelet activation is inhibited at very high heparin concentrations (eg, 100 International Units/mL), as excess heparin disrupts the formation of HIT antigens. HIT antibodies recognize complexes composed of platelet factor 4 (PF4)—a positively charged chemokine found within platelet α-granules—and heparin or certain other polyanions. However, a key problem is that among the many patients who receive heparin and who form anti-PF4/heparin antibodies that are readily detected by enzyme-linked immunosorbent assay (ELISA), only a minority of those antibodies are of the requisite platelet-activating isotype class (IgG), recognize the appropriate antigen site(s), and found in sufficient quantities to trigger platelet activation.