Generation and pathogenicity of anti-platelet factor 4 antibodies: diagnostic implications

Recent studies have elucidated the target antigens for heparin-dependent antibodies. The major one is generated in the presence of platelet factor 4 (PF4) and heparin at a well-defined concentration that allows formation of heparin-PF4 complexes and induces an alteration of the PF4 molecule. It then exposes neoepitopes, which bind the heparin-dependent antibodies. These antibodies are generated only in some heparin-treated patients, and only a subgroup of them develops thrombocytopenia (HIT) sometimes associated with thrombosis (HITT). The major challenge is to understand how antibodies can be generated and why only some of them are pathogenic. The presence of the IgG isotype at a high concentration is an important factor for developing HIT/HITT. The clinical context, which induces accumulation and activation of platelets at pathological sites, is also important for disease occurrence. The presence of antibodies (mainly the IgG isotype) enhances cell-cell interactions and platelet activation followed by platelet accumulation at these sites. Generation and expression of the autoantigen, HPF4 complexes, is a key feature for triggering antibody binding and pathogenicity. Factors contributing to antibody generation and its persistence, and factors contributing to the expression of the autoantigen triggering the disease development are discussed.