Characterization of the humoral immune response in heparin-induced thrombocytopenia.

Recent reports indicate that antibodies associated with heparin-induced thrombocytopenia and thrombosis (HITP) are specific for complexes formed between heparin and the heparin-binding, platelet alpha granule protein, platelet factor 4 (PF4). As with other disorders mediated by immune complexes (IC), the characteristics of the involved immunoglobulins could affect the ability of IC to cause symptoms. We therefore studied the class, subclass, and potency of antibodies specific for heparin:PF4 complexes formed by two groups of patients: one with severe thrombocytopenia, with or without thrombosis, and a positive serotonin release assay (SRA) (Group 1) and another with mild or absent thrombocytopenia, absence of thrombosis, and a negative SRA despite having formed antibodies reactive with heparin:PF4 complexes (Group 2). IgG antibodies were more common in the Group 1 patients (100%) than in Group 2 (46%), whereas IgM antibodies were more common in Group 2 (81%) than in Group 1 (42%) (P = 0.009). About half of each group formed IgA antibodies. In each group, the IgG antibodies were predominantly IgG1 (82%); 42% were IgG3. Only one IgG2 antibody was identified in a total of 52 antibody formers. Antibodies of the IgG class were consistently of higher titer in Group 1 patients than in Group 2 patients (P < 0.001). Recent reports suggest that the H131 form of the Fc gammaRII receptor, which binds preferentially to IgG2 Fc, is found with greater than expected frequency in patients with HITP. Identification of only one IgG2 antibody among 38 antibodies of the IgG class argues against a unique role for antibodies of this subclass in the pathogenesis of HITP. The finding that titers of antibodies in Group 1 patients were a significantly higher titer than in Group 2 patients suggests that development of the full-blown HITP syndrome may require the formation of antibodies of unusually high titer.