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of FcyRIIa-His131 platelets, without significant role for MPS cells (Denomme et al., 1997)

Abbreviations: Arg, arginine; FcyRIIa, FcyIIa receptor; His, histidine; HIT, heparin-induced thrombocytopenia; MPS, mononuclear phagocytic system (reticuloendothelial system); SLE, systemic lupus erythematosus.

Abbreviations: Arg, arginine; FcyRIIa, FcyIIa receptor; His, histidine; HIT, heparin-induced thrombocytopenia; MPS, mononuclear phagocytic system (reticuloendothelial system); SLE, systemic lupus erythematosus.

individuals exhibit considerable variability in their activation by HIT sera (Salem and Van der Weyden, 1983; Pfueller and David, 1986; Warkentin et al., 1992). Second, many patients who form HIT antibodies during heparin treatment do not develop thrombocytopenia (Warkentin et al., 1995, 2005; Amiral et al., 1996; Suh et al., 1997). Third, the inciting role of heparin, a sulfated carbohydrate, suggested that there could be an important role for HIT antibodies of IgG2 subclass, which is the subclass with higher affinity for FcyRIIa-His131 that is predominantly formed in response to carbohydrate antigens (Herrmann et al., 1992). However, HIT epitopes form on the protein PF4 when it undergoes conformation change bound to heparin (see Chapters 5-7). Consequently, it was speculated that the FcyRIIa variant distribution in HIT would differ significantly from a random control population and especially differ from patients who did not develop thrombocytopenia during heparin treatment (Denomme et al., 1997; Bachelot-Loza et al., 1998).

The six studies investigating the role of the FcyRIIa-Arg/His131 variants have not yielded uniform results (Fig. 3). Three studies showed a predominance of the His131 variant in patients with HIT that was significant, compared with control

His131 Gene Frequency 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

Burgess et al., 1995 n=19

Brandt et al., 1995 n=96

Denomme et al., 1997 n=84

Arepally et al., 1997 n=36

Bachelot-Loza et al., 1998 n=25

Carlsson et al., 1998 n=389

HIT subgroup with thrombosis —> HIT subgroup without thrombosis-»

Thrombocytopenic patients with HIT Thrombocytopenic patients without HIT Normal volunteers i—O—' Non-thrombocytopenic patients #—1 Non-thrombocytopenic patients receiving heparin

Genetic Thrombocytopenia

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).

P=0.035 Three studies reporting increased Hislcil frequency in HIT

His131 gene frequency for all patients with HIT (0.499, n=649)

Two studies , reporting no * difference in gene frequency

Largest study reporting no " decreased His frequency in HIT

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