Recent studies have shown that antibodies characteristic of quinine- and quinidine-induced thrombocytopenia sometimes recognize the platelet membrane glycoprotein (GP) complex IIb/IIIa in addition to their well known target, GPIb/IX. We have investigated the frequency with which drug-induced antibodies bind to GPIIb/IIIa and the nature of their target epitopes. In studies of sera from 13 patients sensitive to quinidine or quinine, we found that 10 contained IgG antibodies specific for both GPIb/IX and GPIIb/IIIa, two reacted with GPIb/IX alone, and one reacted with GPIIb/IIIa alone. In all cases, the presence of drug was required for binding of IgG to target GPs. By immunoabsorption, we found that each of five polyspecific sera contained at least two different antibodies, one reactive with GPb/IX and the other with GPIIb/IIIa. Further studies with eight drug- dependent antibodies (DDAb) specific for GPIIb/IIIa showed that three recognized the GPIIb/IIIa complex only, one recognized GPIIb alone, and three recognized GPIIIa alone. The eighth serum appeared to bind to both GPIIIa alone and to an epitope determined by the GPIIb/IIIa complex. The three antibodies specific for GPIIIa alone also reacted with GPIIIa deglycosylated with endo-H, and with the major (61 Kd) fragment obtained by chymotryptic digestion of GPIIIa but failed to react with reduced GPIIIa. These findings demonstrate that, in drug- induced, immunologic thrombocytopenia, the anti-platelet immune response is typically directed against epitopes on both GPIb/IX and GPIIb/IIIa. The three DDAb we studied that were specific for GPIIIa alone recognize epitopes resistant to chymotrypsin and endo-H treatment that are dependent on intrachain disulfide bonding.

Drug-dependent IgG antibodies (DDAb) induced by sulfamethoxazole (SMX) and sulfisoxazole (SIX) were identified by flow cytometry in 15 patients who developed thrombocytopenia while taking one of these medications. Fourteen of the 15 DDAb were specific solely for the glycoprotein (GP)IIb/IIIa complex, and 13 of these reacted wholly or in part with epitopes present only on the intact GPIIb/IIIa heterodimer. None of 12 SMX-induced DDAb cross-reacted with SIX, but one of three SIX-induced antibodies reacted with SMX. Each of 10 SMX-induced DDAb tested reacted with the N1-acetyl metabolite of SMX, but only one reacted fully with the N4-acetyl derivative. Detection of the SMX- and SIX-dependent antibodies was facilitated by using bovine serum albumin (BSA) to achieve suspension of these weakly soluble drugs in an aqueous medium. Our findings indicate that DDAb induced by SMX and SIX, in contrast to those induced by quinidine and quinine, are mainly specific for GPIIb/IIIa and react preferentially with calcium-dependent epitopes present only on the intact GPIIb/IIIa heterodimer.