Antibodies causing thrombocytopenia in patients treated with RGD-mimetic platelet inhibitors recognize ligand-specific conformers of αIIb/β3 integrin. Blood 2012 Jun 28;119(26):6317-25
Date
04/12/2012Pubmed ID
22490676Pubmed Central ID
PMC3383197DOI
10.1182/blood-2012-01-406322Scopus ID
2-s2.0-84863510984 (requires institutional sign-in at Scopus site) 39 CitationsAbstract
Arginine-glycine-aspartic acid (RGD)-mimetic platelet inhibitors act by occupying the RGD recognition site of α(IIb)/β(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 α(IIb)/β(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 α(IIb)/β(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 α(IIb)/β(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.
Author List
Bougie DW, Rasmussen M, Zhu J, Aster RHAuthors
Richard H. Aster MD Professor in the Medicine department at Medical College of WisconsinJieqing Zhu PhD Professor in the Biochemistry department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsAntibodies
CHO Cells
Cricetinae
Cricetulus
Humans
Ligands
Mice
Mice, Inbred BALB C
Models, Biological
Oligopeptides
Peptides
Platelet Aggregation Inhibitors
Platelet Glycoprotein GPIIb-IIIa Complex
Protein Binding
Protein Conformation
Rats
Substrate Specificity
Thrombocytopenia
Tyrosine
