Antibodies causing thrombocytopenia in patients treated with RGD-mimetic platelet inhibitors recognize ligand-specific conformers of alpha(IIb)/beta(3) integrin

作者：Bougie Daniel W^*; Rasmussen Mark; Zhu Jieqing; Aster Richard H

来源：Blood, 2012, 119(26): 6317-6325.

DOI：10.1182/blood-2012-01-406322

Arginine-glycine-aspartic acid (RGD)-mimetic platelet inhibitors act by occupying the RGD recognition site of alpha(IIb)/beta(3) integrin (GPIIb/IIIa), thereby preventing the activated integrin from reacting with fibrinogen. Thrombocytopenia is a well-known side effect of treatment with this class of drugs and is caused by Abs, often naturally occurring, that recognize alpha(IIb)/beta(3) in a complex with the drug being administered. RGD peptide and RGD-mimetic drugs are known to induce epitopes (ligand-induced binding sites [LIBS]) in alpha(IIb)/beta(3) that are recognized by certain mAbs. It has been speculated, but not shown experimentally, that Abs from patients who develop thrombocytopenia when treated with an RGD-mimetic inhibitor similarly recognize LIBS determinants. We addressed this question by comparing the reactions of patient Abs and LIBS-specific mAbs against alpha(IIb)/beta(3) in a complex with RGD and RGD-mimetic drugs, and by examining the ability of selected non-LIBS mAbs to block binding of patient Abs to the liganded integrin. Findings made provide evidence that the patient Abs recognize subtle, drug-induced structural changes in the integrin head region that are clustered about the RGD recognition site. The target epitopes differ from classic LIBS determinants, however, both in their location and by virtue of being largely drug-specific. (Blood. 2012;119(26):6317-6325)

• 出版日期2012-6-28