Characterization of the binding domains on platelet glycoproteins Ib-IX and IIb/IIIa complexes for the quinine/quinidine-dependent antibodies

Abstract

Sera of 12 patients with quinine/quinidine-induced thrombocytopenia showed drug-dependent antibody binding to glycoprotein (GP) Ib-IX complex. The reaction with GPIb-IX complex of 11 of these 12 sera was strongly inhibited by the complex-specific monoclonal antibodies (MoAbs) AK1 and SZ1. The exception was a quinine-induced serum designated BU. The reaction of the six quinidine-induced sera was also partially blocked by an anti-GPIX MoAb, FMC25. Only 3 of the 12 patient sera showed drug-dependent antibody binding to GPIIb/IIIa, which was strongly inhibited by the anti-GPIIIa MoAb 22C4, and the anti-GPIIb alpha MoAb SZ22. With detergent-solubilized Serratia metalloprotease- treated platelets, quinine/quinidine-induced sera, except BU, immunoprecipitated a membrane-bound proteolytic fragment of GPIb-IX complex. In contrast, BU immunoprecipitated glycocalicin and a 40-Kd peptide tail fragment of GPIb alpha from the cell supernatant. Using purified GPIb-IX complex or its components as the target antigen, all the quinine-induced sera, except BU, immunoprecipitated GPIb-IX complex but failed to immunoprecipitate GPIb, GPIX, or the complex reformed from GPIb and GPIX. The quinidine-induced sera strongly immunoprecipitated purified GPIb-IX complex, weakly immunoprecipitated purified GPIX and the recombined complex, but did not immunoprecipitate purified GPIb. The combined data suggest that one quinine-dependent antibody (BU) recognizes an epitope in the peptide tail region of GPIb alpha and the other five quinine-dependent antibodies react with a complex-specific epitope on the membrane-associated region of GPIb-IX complex, whereas each of the six quinidine-induced sera contain two drug-dependent antibodies, one reactive with the GPIb-IX complex- specific epitope and the other reactive with GPIX. The binding domain(s) on GPIIb/IIIa for the quinine/quinidine-dependent antibodies appear to be sterically close to the epitopes for 22C4 and SZ22.

Glycoprotein Ib/IX complex is the target in rifampicin‐induced immune thrombocytopenia

“…These results suggest that the binding epitope of the antibody is identical or is located very close to the domains recognized by the mAbs SZ1 and BL-H6, as the antibody cross-blocked the binding of both mAbs to GPIX. This notion is further supported by two recent studies showing that the binding of SZ1 to GPIb/IX complex was also blocked by six different quinidinedependent antibodies (Chong et al, 1991) and a ranitidinedependent antibody (Gentilini et al, 1998).…”

Ceftriaxone causes drug‐induced immune thrombocytopenia and hemolytic anemia: characterization of targets on platelets and red blood cells

“…Most DDAbs specific for PLTs bind to epitopes on the GPIIb/IIIa and/or GPIb/IX complexes. 4,7,10,11 However, the binding pattern of DDAbs on either GP is heterogeneous. Whereas some quinidine-dependent DDAbs against GPIIb/IIIa required the intact complex for binding, others were able to precipitate dissociated GPIIIa.…”

“…11 Inhibition studies with panels of MoAbs against the respective GP revealed evidence for various DDAb epitopes on GPIIb/ IIIa and GPIb/IX. 4,11 Recently, Peterson et al 32 demonstrated that substitution of the amino acids 50, 62, and 66 of GPIIIa abolished the binding of a subgroup of GPIIIaspecific quinidine DDAbs. GPIIb/IIIa-specificity of ceftriaxone DDAbs in Patient 1 could be demonstrated by MAIPA assay and with stable CHO transfectants.…”

“…12,15 The latter hypothesis is supported by the observation of antibody clones with different targets on the same cell type in patients with DITP as well as in autoimmune thrombocytopenia. 4,11,16 Ceftriaxone is a third-generation cephalosporin that has been reported to cause DIHA in numerous cases (for review, see Seltsam and Salama,17 and Arndt and Garratty 18 ). In some cases, DDAbs against in-vivo metabolites of ceftriaxone could be detected either exclusively or together with DDAbs against the drug itself.…”

Sulfamethoxazole‐induced thrombocytopenia masquerading as posttransfusion purpura: a case report

“…Although at least 100 drugs have been implicated in DITP, convincing data for a causal relationship between medications and immunemediated thrombocytopenia exists for a more selective group of drugs, 19 which include quinine and quinidine (cinchona alkaloid derivatives), penicillin, vancomycin, abciximab, ranitidine, sulfonamides, gold salts, thiazide diuretics (which can also mediate megakaryocyte suppression), and antirheumatic and oral antidiabetic drugs. [19][20][21][22][23][24] Rapid development of thrombocytopenia typically manifests 7 days after starting a new drug or within 2 to 3 days of reexposure.…”