Antibodies causing thrombocytopenia in patients treated with RGD-mimetic platelet inhibitors recognize ligand-specific conformers of αIIb/β3 integrin

Pro32Pro33 Mutations in the Integrinβ3PSI Domain Result inαIIbβ3Priming and Enhanced Adhesion: Reversal of the Hypercoagulability Phenotype by the Src Inhibitor SKI-606

“…Here, we focused on the study of a common integrin b 3 coding polymorphism, Leu33Pro within the aIIbb 3 integrin (Newman et al, 1989). Flow cytometry studies utilizing anti-Leu33 b 3 antisera from Pro33 thrombocytopenia patients reveal conformational changes in an epitope located between residues 9 and 50, likely due to the formation of a diproline sequence in Src Mediates Integrin b 3 Pro33-Induced Hyperaggregability the PSI domain (Barron-Casella et al, 1999;Bougie et al, 2012). To mimic the structural changes induced by the Leu33Pro mutation in humans, we introduced the Pro32-Pro33 sequence in the mouse Itgb3 locus, replacing the endogenous Ser32Gln33.…”

Drug-induced thrombocytopenia: MIBS trumps LIBS

“…However, Bougie and colleagues found that the 2 drugdependent antibodies did cross-react in approximately 30% of patients. 1 Their findings suggest that it might not be safe to administer tirofiban to a patient with eptifibatide-induced thrombocytopenia and vice versa. One approach is to assess antibody cross-reactivity before administration of an alternative RGD mimetic as some clinical laboratories may be able to detect eptifibatide-and tirofibandependent antibodies 4 and assess antibody cross-reactivity using flow cytometry.…”

“…1 A t the end of the 1990s, 2 prospective trials compared autologous stem cell transplantation (auto-SCT) with myeloablative allo-SCT in MM. 2,3 In both of these, extremely high rates of transplant-related mortality (TRM) were observed in the allogeneic arms, ranging from 30% despite partial T-cell depletion in the study conducted by the HOVON group, 2 up to 53% in the United States Intergroup trial (S9321), in which T-cell depletion was not carried out.…”

“…[5][6][7][8][9][10][11] Lokhorst et al performed a donor versus no-donor analysis of patients included in the phase 3 HOVON-50 MM trial. 1 After a single auto-SCT, eligible patients were randomized according to the availability of an HLA-identical sibling to receive either maintenance therapy consisting of thalidomide or ␣-interferon or RIC allo-SCT after low-dose 2 Gy total body irradiation. Importantly, the trial included a large number of patients, and the median follow-up, which exceeds 6 years, is long enough to draw reliable conclusions.…”

“…3,7,8 Here, Bougie and colleagues directly investigated this issue and found that patient antibodies did not recognize LIB determinants as previously expected but instead recognized conformational changes in ␣ IIb ␤ 3 induced by the drug. 1 In the majority of patients with eptifibatide-and tirofiban-induced thrombocytopenia (30 of 43 patients), antibody binding was drug specific and only occurred when the For personal use only. on May 12, 2018. by guest www.bloodjournal.org From integrin complexed with the drug that caused the thrombocytopenia.…”