PF4 complexed with heparin is the major antigen involved in HIT. Understanding the mechanisms for generating heparin-dependent antibodies, and how these antibodies become pathogenic, offers new approaches for diagnosis and management of HIT. Only a subset of antibodies to PF4-H exhibit a pathogenic effect by triggering thrombocytopenia and/or thrombosis, particularly IgG antibodies with the highest affinity for PF4-H. The conditions that permit formation of the PF4-H target antigens involve the type of heparin used, the dose and duration of therapy, and the clinical context of the treated patient. Immunoreactive complexes between PF4 and heparin are formed only under certain conditions, with their formation in high concentrations facilitated if underlying disease favors platelet activation and release. Similar conditions enhance the pathogenicity of the HIT antibodies generated. These considerations help to unravel the seemingly random generation of HIT antibodies among heparin-treated patients as well as the apparent chance occurrence of thrombocytopenia and thrombotic events. In addition, some HIT episodes could be associated with preexisting antibodies to chemokines such as IL-8, NAP-2, or possibly, even PF4. The use of heparin then only constitutes the abrupt trigger of pathogenicity by focusing these antibodies onto targeted blood cells and ECs. This could be the explanation for atypical presentations of HIT that can occur with pathological states such as malignancy, major surgery/inflammation, or infections. Understanding how heparin-dependent antigens can induce antibody generation, how these antibodies can become pathogenic in a subset of patients, and how heparin can trigger pathological effects for naturally-occurring antichemokine antibodies, can improve recognition and management of these complications of heparin therapy. This includes the development of more appropriate diagnostic laboratory assays for this life-threatening iatrogenic complication of heparin therapy.

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