Kroll H, Sun Q H, Santoso S
Institute for Clinical Immunology and Transfusion Medicine, Justus Liebig University Giessen, Germany.
Blood. 2000 Aug 15;96(4):1409-14.
Drug-induced immune thrombocytopenia (DITP) is a serious complication of drug treatment. Previous studies demonstrated that most drug-dependent antibodies (DDAbs) react with the platelet membrane glycoprotein (GP) complexes IIb/IIIa and Ib/IX/V. We analyzed the sera from 5 patients who presented with DITP after intake of carbimazole. Notably, thrombocytopenia induced by carbimazole was relatively mild in comparison to patients with DITP induced by quinidine. The sera reacted with platelets in an immunoassay on addition of the drug. In immunoprecipitation experiments with biotin-labeled platelets and endothelial cells, reactivity with the platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31) could be demonstrated, whereas neither GPIIb/IIIa nor GPIb/IX was precipitated in the presence of the drug. These results could be confirmed by GP-specific immunoassay (MAIPA) using monoclonal antibodies (mabs) against PECAM-1. In addition, the binding of DDAbs could be abolished by preincubation with soluble recombinant PECAM-1. Carbimazole-dependent antibodies showed similar reactivity with platelets carrying the Leu(125) and Val(125) PECAM-1 isoforms, indicating that this polymorphic structure, which is located in the first extracellular domain, is not responsible for the epitope formation. Binding studies with biotin-labeled mutants of PECAM-1 and analysis of sera with mabs against different epitopes on PECAM-1 in MAIPA assay suggested that carbimazole-dependent antibodies prominently bound to the second immunoglobulin homology domain of the molecule. Analysis of 20 sera from patients with quinidine-induced thrombocytopenia by MAIPA assay revealed evidence that DDAbs against PECAM-1 are involved in addition to anti-GPIb/IX and anti-GPIIb/IIIa. We conclude that PECAM-1 is an important target GP in DITP. (Blood. 2000;96:1409-1414)
药物性免疫性血小板减少症（DITP）是药物治疗的一种严重并发症。先前的研究表明，大多数药物依赖性抗体（DDAbs）与血小板膜糖蛋白（GP）复合物IIb/IIIa和Ib/IX/V发生反应。我们分析了5例服用卡比马唑后出现DITP患者的血清。值得注意的是，与奎尼丁诱导的DITP患者相比，卡比马唑诱导的血小板减少相对较轻。在免疫测定中加入药物后，血清与血小板发生反应。在使用生物素标记的血小板和内皮细胞进行的免疫沉淀实验中，可证明与血小板内皮细胞黏附分子-1（PECAM-1，CD31）发生反应，而在药物存在的情况下，GPIIb/IIIa和GPIb/IX均未沉淀。使用抗PECAM-1的单克隆抗体（mabs）进行的GP特异性免疫测定（MAIPA）可以证实这些结果。此外，通过与可溶性重组PECAM-1预孵育可消除DDAbs的结合。卡比马唑依赖性抗体与携带Leu(125)和Val(125) PECAM-1同种型的血小板表现出相似的反应性，表明位于第一个细胞外结构域的这种多态性结构不是表位形成的原因。在MAIPA测定中，使用生物素标记的PECAM-1突变体进行结合研究以及用针对PECAM-1不同表位的mabs分析血清表明，卡比马唑依赖性抗体主要结合到该分子的第二个免疫球蛋白同源结构域。通过MAIPA测定分析20例奎尼丁诱导的血小板减少症患者的血清发现，除了抗GPIb/IX和抗GPIIb/IIIa外，还存在针对PECAM-1的DDAbs。我们得出结论，PECAM-1是DITP中的一个重要靶标糖蛋白。（《血液》。2000年；96:1409 - 1414）
