Heparin-associated thrombocytopenia is mediated by antibody recognition of a neoantigen on heparin/platelet factor 4 complexes; the antibody then activates the platelet by the FcgammaRIIA receptor.
Three aims are proposed: 1. Characterizing the sites on PF4 involved in the reaction. Sites will be defined using recombinant wild and mutated PF4 and chimeras of PF4 and the related chemokine, beta- thromboglobulin, using antibodies of affected patients; 2. Defining the immune complex/FcR interactions : IgG1 and IgG3 antibodies are thought to mediate platelet destruction through interaction with FcgammaR on macrophages. IgG2 antibodies react less well with macrophage FcR but activate platelets in patients with an allomorphic variant -His131 . They propose to study both the IgG response and the FcgammaR phenotype of patients with HAT, and with and without thrombocytopenia; 3. Defining the molecular nature of the antibodies: Antigen specific clones of lymphocytes will be isolated from patients and the antibody genetics will be studied in detail to seek evidence of antigen mediated selection of the HAT immune response. Such antibodies could provide basis for analysis of the antigen recognition site, and of the antibody - heparin/PF4 interaction. This in turn could lead to the finding of anti- idiotype antibodies of diagnostic and perhaps therapeutic usefulness.
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