Cunha P D, Lord R S, Johnson S T, Wilker P R, Aster R H, Bougie D W
West Michigan Cancer Center, Kalamazoo, Michigan, USA.
Transfusion. 2000 Jun;40(6):663-8. doi: 10.1046/j.1537-2995.2000.40060663.x.
Immune hemolytic anemia can be caused by sensitivity to many different drugs. In some instances, the sensitizing compound can be identified by in vitro testing, but results are often negative. One reason for this is that a drug metabolite formed in vivo can be the sensitizing agent, but the responsible metabolites have rarely been identified at a chemical level. This report describes a patient who developed severe, Coombs-positive hemolytic anemia on two occasions after taking the nonsteroidal anti-inflammatory drug etodolac. Studies were performed to characterize etodolac metabolites to which this patient was sensitive.
Serum was tested for antibody in the presence and absence of drug using conventional methods and urine from individuals taking etodolac as a source of drug metabolites. Urinary metabolites of etodolac were identified by high-pressure liquid chromatography analysis. Glucuronide conjugates of etodolac and the 6-OH metabolite of etodolac were synthesized in a rat liver microsomal system to obtain reference standards.
The patient's serum gave only trace (+/-) reactions with normal RBCs in the presence of etodolac but reacted strongly (4+) in the presence of urine from an individual taking this drug. The active urinary metabolites were identified as etodolac glucuronide and 6-OH etodolac glucuronide.
This patient appears to have experienced acute, severe immune hemolytic anemia on two occasions because of sensitivity to the glucuronides of etodolac and 6-OH etodolac. In patients suspected of having drug-induced immune hemolytic anemia, RBC-reactive antibodies can sometimes be detected by using urine from an individual taking the implicated medication as the source of drug metabolites in in vitro reactions. For patients who present with acute immune hemolysis, a careful history of drug exposure should be taken, and, where indicated, confirmatory testing should be performed to identify the sensitizing drug and prevent inadvertent reinduction of hemolysis at a later time.
免疫性溶血性贫血可由对多种不同药物的敏感性引起。在某些情况下，致敏化合物可通过体外试验鉴定，但结果往往为阴性。其原因之一是体内形成的药物代谢产物可能是致敏剂，但在化学层面上，很少能鉴定出相关代谢产物。本报告描述了一名患者，在服用非甾体抗炎药依托度酸后两次发生严重的、抗人球蛋白试验阳性的溶血性贫血。进行了相关研究以鉴定该患者敏感的依托度酸代谢产物。
使用传统方法在有药物和无药物的情况下检测血清中的抗体，并使用服用依托度酸个体的尿液作为药物代谢产物来源。通过高压液相色谱分析鉴定依托度酸的尿代谢产物。在大鼠肝微粒体系统中合成依托度酸的葡萄糖醛酸结合物和依托度酸的6-羟基代谢产物，以获得参考标准品。
在有依托度酸存在的情况下，患者血清与正常红细胞仅产生微量（±）反应，但在有服用该药物个体的尿液存在时反应强烈（4+）。活性尿代谢产物被鉴定为依托度酸葡萄糖醛酸和6-羟基依托度酸葡萄糖醛酸。
该患者似乎两次因对依托度酸和6-羟基依托度酸的葡萄糖醛酸敏感而发生急性、严重的免疫性溶血性贫血。在疑似药物性免疫性溶血性贫血的患者中，有时可通过使用服用相关药物个体的尿液作为体外反应中药物代谢产物来源来检测红细胞反应性抗体。对于出现急性免疫性溶血的患者，应仔细询问药物暴露史，并在必要时进行确证试验，以鉴定致敏药物并防止日后无意中再次诱发溶血。
