Acute thrombocytopenia after treatment with tirofiban or eptifibatide is associated with antibodies specific for ligand-occupied GPIIb/IIIa
Acute thrombocytopenia after treatment with tirofiban or eptifibatide is associated with antibodies specific for ligand-occupied GPIIb/IIIa
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DOI：
10.1182/blood.v100.6.2071.h81802002071_2071_2076
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发表时间：
2002-09-15
期刊：
影响因子：
20.3
通讯作者：
Aster, RH
中科院分区：
文献类型：
--
作者：
Bougie, DW;Wilker, PR;Aster, RH
急性血小板减少症是公认的GPIIb/IIIa抑制剂治疗的并发症，其原因尚不清楚。我们研究了9例在使用GPIIb/IIIa抑制剂替罗非班（4例）和依替巴肽（5例）治疗数小时内发生严重血小板减少（血小板小于25 × 10(9)/L）的患者。在每个患者中，急性期血清含有高滴度（范围1:80-1:20 000）IgG抗体，仅在治疗中使用的药物存在时才与糖蛋白IIb/IIIa复合物发生反应。4名患者以前曾接受过同样的药物治疗，但5名患者之前没有接触过这种药物。后两例患者的预处理血清样品中含有与治疗后鉴定的药物依赖性抗体相似的抗体。在100名随机选择的健康献血者中没有发现替罗非班或依替巴肽依赖抗体，在接受替罗非班或依替巴肽治疗的23名患者中，只有2名没有明显的血小板减少症的患者有极弱的（滴度为1:2）替罗非班依赖抗体。在前期研究中，9种抗体识别GPIIb/IIIa上与患者敏感的抑制剂络合的多个靶表位，表明它们不能都对药物结合位点具有特异性。研究结果表明，使用替罗非班或依替巴肽后的急性血小板减少症可能是由“自然产生”的药物依赖性抗体引起的，或者是由先前暴露于药物引起的。这些抗体可能是小鼠单克隆抗体的人类似物，可以识别GPIIb/IIIa异源二聚体与配体模拟药物反应时诱导的配体诱导结合位点（LIBS）。
Acute thrombocytopenia is a recognized complication of treatment with GPIIb/IIIa inhibitors whose cause is not yet known. We studied 9 patients who developed severe thrombocytopenia (platelets less than 25 x 10(9)/L) within several hours of treatment with the GPIIb/IIIa inhibitors tirofiban (4 patients) and eptifibatide (5 patients). In each patient, acute-phase serum contained a high titer (range, 1:80-1:20 000) IgG antibody that reacted with the glycoprotein IIb/IIIa complex only in the presence of the drug used in treatment. Four patients had been previously treated with the same drug, but 5 had no known prior exposure. Pretreatment serum samples from 2 of the latter patients contained drug-dependent antibodies similar to those identified after treatment. No tirofiban- or eptifibatide-dependent antibodies were found in any of 100 randomly selected healthy blood donors, and only 2 of 23 patients receiving tirofiban or eptifibatide who did not experience significant thrombocytopenia had extremely weak (titer, 1:2) tirofiban-dependent antibodies. In preliminary studies, evidence was obtained that the 9 antibodies recognize multiple target epitopes on GPIIb/IIIa complexed with the inhibitor to which the patient was sensitive, Indicating that they cannot all be specific for the drug-binding site. The findings indicate that acute thrombocytopenia after the administration of tirofiban or eptifibatide can be caused by drug-dependent antibodies that are "naturally occurring" or are Induced by prior exposure to drug. These antibodies may be human analogs of mouse monoclonal antibodies that recognize ligand-induced binding sites (LIBS) induced In the GPIIb/IIIa heterodimer when It reacts with a ligand-mimetic drug.