An antibody from a patient with ranitidine-induced thrombocytopenia recognizes a site on glycoprotein IX that is a favored target for drug-induced antibodies.
Although thrombocytopenia associated with the use of histamine H2 receptor (H2R) antagonists has been described, a drug-dependent, platelet-reactive antibody has not previously been identified in such cases. We studied serum from a patient who developed acute, severe thrombocytopenia after exposure to the H2 receptor antagonist, ranitidine, and identified an antibody that reacted with normal platelets in the presence of this drug at pharmacologic concentrations. In flow cytometric and immunoprecipitation studies, the antibody was shown to be specific for the glycoprotein Ib/IX complex (GPIb/IX). From the pattern of monoclonal antibody (MoAb) inhibition and the reactions of antibody with Chinese hamster ovary (CHO) cells transfected with GPIX and GPIbbeta, we found that the patient's antibody is specific for an epitope on GPIX close to, or identical with a site recognized by the MoAb SZ1 that is a common target for antibodies induced by quinine and quinidine, drugs structurally unrelated to ranitidine. These findings provide evidence that immune thrombocytopenia can be caused by sensitivity to an H2 R antagonist and suggest that the SZ1 binding site on GPIX may be a common target for drug-induced antibodies. Further studies of the epitope for which SZ1 is specific may provide clues to the mechanism(s) by which drugs promote tight binding of antibody to a membrane glycoprotein and cause platelet destruction in patients with drug sensitivity.
Gentilini
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G
Department of Medicine, Medical College of Wisconsin and the Blood Research Institute, The Blood Center of Southeastern Wisconsin, Milwaukee, WI 53226-3548, USA.
Curtis
B R
BR
Aster
R H
RH
D000368:Aged; D000818:Animals; D000897:Anti-Ulcer Agents / Q000009:adverse effects* / Q000737:chemistry; D000911:Antibodies, Monoclonal / Q000276:immunology; D000918:Antibody Specificity; D000937:Antigen-Antibody Reactions; D001323:Autoantibodies / Q000276:immunology*; D001327:Autoimmune Diseases / Q000139:chemically induced* / Q000276:immunology; D001792:Blood Platelets / Q000276:immunology*; D016466:CHO Cells; D002927:Cimetidine / Q000737:chemistry / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D000939:Epitopes / Q000276:immunology; D015738:Famotidine / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D006635:Histamine H2 Antagonists / Q000009:adverse effects* / Q000737:chemistry; D006801:Humans; D015394:Molecular Structure; D016567:Nizatidine / Q000737:chemistry / Q000494:pharmacology; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D011233:Precipitin Tests; D011487:Protein Conformation; D011802:Quinidine / Q000009:adverse effects; D011803:Quinine / Q000009:adverse effects; D011899:Ranitidine / Q000009:adverse effects* / Q000737:chemistry; D011993:Recombinant Fusion Proteins / Q000276:immunology; D013329:Structure-Activity Relationship; D013921:Thrombocytopenia / Q000139:chemically induced* / Q000276:immunology; D014162:Transfection
D000897:Anti-Ulcer Agents; D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D000939:Epitopes; D006635:Histamine H2 Antagonists; D019038:Platelet Glycoprotein GPIb-IX Complex; D011993:Recombinant Fusion Proteins; D015738:Famotidine; D002927:Cimetidine; D011899:Ranitidine; D011803:Quinine; D011802:Quinidine; D016567:Nizatidine