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FIGURE 3 FcyRIIa-His131 gene frequencies in six studies of HIT are shown: The first four studies were from North American centers and the last two from Europe. Although the first three studies showed predominance of His131 in patients with HIT, the last study showed predominance of Arg131 in patients with HIT complicated by thrombosis. A complicating feature is the difference in gene frequencies between certain control populations [e.g., between Denomme et al., (1997) and Carlsson et al. (1998)]. Not shown in the figure is the significant difference between control patients in the studies by Carlsson and Brandt (p = 0.013).

patients. Together with evidence that HIT antibodies preferentially activate platelets in vitro from individuals bearing the FcyRIIa-His 1 variant (Denomme et al., 1997; Bachelot-Loza et al., 1998), it was suggested that FcyRIIa-His131 predominance could reflect a greater potential for these platelets to be activated in vivo by HIT antibodies (Table 2). Two relatively small studies did not show any significant differences in the Arg/His131 variants between HIT patients and controls.

However, the largest of the six studies, involving 389 patients (i.e., more than the 260 HIT patients reported in the previous five studies combined), showed an increase in the frequency of the Arg131, rather than the His131, variant in patients with HIT (Carlsson et al., 1998). Moreover, these workers observed that the increase in FcyRII-Arg131 variant occurred only in the subset of patients whose HIT was complicated by thrombosis. These investigators proposed that reduced clearance of IgG-containing immune complexes by phagocytic cells bearing FcyRIIa-Arg131 leads to greater immune complex-dependent activation of platelets, thus predisposing one to thrombosis (Table 2). Although Arepally et al. (1997) did not observe a significant increase in the FcyRIIa-Arg131 variant among HIT patients with thrombosis, their subset of HIT patients with thrombosis was much smaller than that reported by Carlsson (23 vs. 68 patients). On the other hand, when Pouplard and colleagues (1999) examined the FcyRIIa-Arg/His131 variant frequency among patients who formed antibodies against PF4-H following cardiac surgery, they noted that platelet levels were significantly lower only in the homozygous FcyRIIa-Arg/Arg131 group, when compared with patients who did not form antibodies.

The explanation for the differences among these various studies is not readily apparent. However, a complicating aspect is noted in Figure 3: the frequency of the FcyRIIa-His131 variant is higher in the European control populations (Bachelot-Loza et al., 1998; Carlsson et al., 1998), compared with the North American and Australian controls (Burgess et al., 1995; Brandt et al., 1995; Denomme et al., 1997; Arepally et al., 1997), an observation consistent with population allele frequencies reported by Rascu et al. (1997). Indeed, pairwise X2 analysis for the frequency of the FcyRIIa-His131 variant among the various controls shows that the control population of Carlsson's study differs from that reported by Denomme and Brandt (Fig. 3). The FcyRIIa-Arg/His131 variants differ among populations: in whites and African Americans, the allele frequencies have roughly a 50:50 balance (Osborne et al., 1994; Lehrnbecher et al., 1999). In contrast, in the Japanese and Chinese populations, the FcyRIIa-His131 allele frequency is approximately 75% (Rascu et al., 1997; Osborne et al., 1994). It is possible that unrecognized differences in population between HIT patients and controls could be important. For example, whereas samples from HIT patients could be referred from a wider geographic area, control patients might have been obtained from a localized area. None of the six studies reported on the FcyRIIa-Arg/His131 variant distribution among heparin-treated patients who formed HIT antibodies but who did not develop thrombocytopenia (i.e., the ideal control group for assessing the influence of the FcyRIIa polymorphism).

In summary, the role of the FcyRIIa-Arg/His131 variants in contributing to the pathogenesis of HIT remains controversial. Regardless of its ultimate resolution, the elucidation of the biological basis for differences in frequency of FcyRIIa phenotype between HIT patients, with or without thrombosis, and control subjects will provide new insights into the pathogenesis of immune-mediated disease.

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