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.