Billheimer Jeffrey T, Dicker Ira B, Wynn Richard, Bradley Jodi D, Cromley Debra A, Godonis Helen E, Grimminger Lisa C, He Bokang, Kieras Cathy J, Pedicord Donna L, Spitz Susan M, Thomas Beth E, Zolotarjova Nina I, Gorko Mary A, Hollis Gregory F, Daly Robert N, Stern Andrew M, Seiffert Dietmar
Department of Chemical Enzymology, Bristol-Myers Squibb Pharma Company, Wilmington, DE 19880-0400, USA.
Blood. 2002 May 15;99(10):3540-6. doi: 10.1182/blood.v99.10.3540.
Glycoprotein (GP) IIb/IIIa antagonists are effective therapeutic agents, but elicit thrombocytopenia with a frequency that approaches 2%. Here, we provide evidence that thrombocytopenia in humans treated with the GP IIb/IIIa antagonist roxifiban is immune mediated. Two patients underwent conversion to a highly positive drug-dependent antibody (DDAB) status temporally associated with thrombocytopenia. Despite the continued presence of DDABs, the fall in platelet count was reversed by discontinuation of drug treatment, pointing to the exquisite drug dependency of the immune response. DDABs appear to bind to neoepitopes in GP IIb/IIIa elicited on antagonist binding. This information was used to develop an enzyme-linked immunosorbent assay (ELISA) for DDAB using solid-phase GP IIb/IIIa. A high level of specificity is indicated by the observation that DDAB binding is dependent on the chemical structure of the GP IIb/IIIa antagonist and that only 2% to 5% of human blood donors and 5% of chimpanzees present with pre-existing DDABs. Furthermore, none of 108 nonthrombocytopenic patients from the phase II roxifiban study showed an increase in antibody titer. Absorption of thrombocytopenia plasma with platelets reduced the DDAB ELISA signal, indicating that the test detects physiologically relevant antibodies. Screening patients for pre-existing or increasing DDAB titer during treatment with GP IIb/IIIa antagonists may reduce the incidence of drug-induced thrombocytopenia.
糖蛋白（GP）IIb/IIIa拮抗剂是有效的治疗药物，但会引发血小板减少症，其发生率接近2%。在此，我们提供证据表明，接受GP IIb/IIIa拮抗剂罗昔非班治疗的人类患者出现的血小板减少症是免疫介导的。两名患者在出现血小板减少症的同时，暂时转变为高度阳性的药物依赖性抗体（DDAB）状态。尽管DDAB持续存在，但通过停止药物治疗，血小板计数的下降得以逆转，这表明免疫反应对药物具有高度依赖性。DDAB似乎与拮抗剂结合后在GP IIb/IIIa中引发的新表位结合。利用这一信息，我们开发了一种使用固相GP IIb/IIIa检测DDAB的酶联免疫吸附测定（ELISA）方法。观察结果表明，DDAB的结合依赖于GP IIb/IIIa拮抗剂的化学结构，且仅2%至5%的人类献血者和5%的黑猩猩存在预先存在的DDAB，这表明该方法具有高度特异性。此外，罗昔非班II期研究中的108名非血小板减少症患者均未出现抗体滴度升高的情况。用血小板吸收血小板减少症患者的血浆可降低DDAB ELISA信号，这表明该检测方法能检测到生理相关抗体。在用GP IIb/IIIa拮抗剂治疗期间，对患者进行预先存在或不断升高的DDAB滴度筛查，可能会降低药物诱导的血小板减少症的发生率。
