Fc gamma RIIA H/R 131 polymorphism, subclass-specific IgG anti-heparin/platelet factor 4 antibodies and clinical course in patients with heparin-induced thrombocytopenia and thrombosis.
The explanation why only a subset of patients with heparin-induced thrombocytopenia (HIT) develop clinically apparent thromboses (HITT) remains uncertain. It has been proposed that platelet activation induced by cross-linking of Fc gamma RIIA by anti-heparin/platelet factor 4 (PF4) antibodies is central to the pathogenesis of thrombosis. The observation that a common functional polymorphism of Fc gamma RIIA, involving either an arginine (R) or histidine (H) at amino acid 131, may underlie disease susceptibility prompted us to investigate the prevalence of receptor isoforms in patients with HIT and HITT. Furthermore, because these isoforms reportedly differ in their avidity for immune complexes containing human IgG2, we also analyzed sera from patients with HIT and HITT for the prevalence of various subclass-specific IgG anti-heparin/PF4 antibodies. No difference in the allele frequency of Fc gamma RIIA-H131 or R131 was identified among 13 patients with HIT or 23 with HITT compared with 102 controls (chi 2 = 1.21, P = .8). Furthermore, although most patients had IgG2 antibodies (62%), IgG, was the predominant subclass in 30 of the 34 patients with IgG anti-heparin/PF4 antibodies and in 12 was the exclusive subclass found. Also, there was no association between the concordance of IgG2 anti-heparin/ PF4 antibodies and the expression of Fc gamma RIIA-H131 in patients with HITT compared with patients with thrombocytopenia alone. These results make it unlikely that the Fc gamma RIIA-H131 isoform or IgG2 anti-heparin/PF4 antibodies are required to develop HITT, suggesting that factors in addition to cross-linking of Fc gamma RIIA receptors contribute to the pathogenesis of thrombosis in patients with heparin-dependent antiplatelet: antibodies.
Arepally, G; McKenzie, SE; Jiang, XM; Poncz, M; Cines, DB
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