title: Early eradication of factor VIII inhibitor in patients with congenital hemophilia A by immune tolerance induction with a high dose of immunoglobulin.
abstract: The production of factor VIII (FVIII) inhibitory antibodies is a serious problem in patients with hemophilia A. Immune tolerance induction (ITI) is the only strategy proven to eradicate persistent inhibitors and has been shown to be successful in 70 % of patients with hemophilia A. However, a minority of hemophilia patients present life-long inhibitors. To eliminate such inhibitors, we designed an intravenous immunoglobulin (IVIG) strategy in combination with high dose recombinant FVIII for ITI in hemophilia A children with inhibitors. Four previously untreated patients produced inhibitors within 16 exposures to FVIII. The peak inhibitor titers in these patients ranged from 3 to 14 BU/mL. The patients received ITI combined with IVIG within 1.5 months after the inhibitors were detected. All patients showed a negative titer for inhibitors by 28 days, with no anamnestic responses. The recovery of FVIII in the plasma concentration was normalized within three months after initiation of ITI. An additional course of IVIG administration led to induction of complete tolerance by 20 months after initiation of ITI therapy in all patients. ITI treatment with high-dose FVIII combined with IVIG may be effective for the early elimination of inhibitors.
authors.affiliation: Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Mizoguchi
authors.affiliation: Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Furue
authors.affiliation: Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Kagawa
authors.affiliation: Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
authors.forename: Ikue
authors.initials: I
authors.lastname: Chijimatsu
authors.affiliation: Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
authors.forename: Keita
authors.initials: K
authors.lastname: Tomioka
authors.affiliation: Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
authors.forename: Maiko
authors.initials: M
authors.lastname: Shimomura
authors.affiliation: Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Imanaka
authors.affiliation: Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
authors.forename: Shiho
authors.initials: S
authors.lastname: Nishimura
authors.affiliation: Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Saito
authors.affiliation: Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
authors.forename: Mizuka
authors.initials: M
authors.lastname: Miki
authors.affiliation: Department of Pediatrics, Miyoshi Central Hospital, Miyoshi, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ono
authors.affiliation: Department of Pediatrics, Chugoku Rousai Hospital, Kure, Japan.
authors.forename: Nakao
authors.initials: N
authors.lastname: Konishi
authors.affiliation: Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawaguchi
authors.affiliation: Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan. masak@hiroshima-u.ac.jp.
authors.forename: Masao
authors.initials: M
authors.lastname: Kobayashi
mesh_terms: D000293:Adolescent; D000906:Antibodies / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D005169:Factor VIII / Q000276:immunology* / Q000627:therapeutic use*; D006467:Hemophilia A / Q000188:drug therapy* / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects*; D016756:Immunoglobulins, Intravenous / Q000276:immunology / Q000627:therapeutic use*; D007223:Infant; D011994:Recombinant Proteins / Q000276:immunology / Q000627:therapeutic use
chemical_list: D000906:Antibodies; D016756:Immunoglobulins, Intravenous; D011994:Recombinant Proteins; C078147:F8 protein, human; D005169:Factor VIII
keywords: Hemophilia; ITI; IVIG; Inhibitors
references.citation: Br J Haematol. 2010 Sep;150(5):515-28
references.pmid: 20573153
references.citation: Lancet. 1984 Oct 6;2(8406):765-8
references.pmid: 6148519
references.citation: Haematologica. 2000 Oct;85(10 Suppl):45-7
references.pmid: 11187870
references.citation: Semin Hematol. 1994 Apr;31(2 Suppl 4):62-4
references.pmid: 7939781
references.citation: Blood. 2012 Feb 9;119(6):1335-44
references.pmid: 22101900
references.citation: J Thromb Haemost. 2011 Nov;9(11):2229-34
references.pmid: 21883884
references.citation: N Engl J Med. 2013 Jan 17;368(3):231-9
references.pmid: 23323899
references.citation: Haemophilia. 1999 Jan;5(1):32-9
references.pmid: 10215945
references.citation: Hamostaseologie. 2010 Nov;30 Suppl 1:S119-21
references.pmid: 21042665
references.citation: Blood Coagul Fibrinolysis. 2015 Sep;26(6):604-12
references.pmid: 25886836
references.citation: Thromb Haemost. 2002 Jan;87(1):52-7
references.pmid: 11848456
references.citation: Haematologica. 2001 Nov;86(11):1186-93
references.pmid: 11694405
references.citation: Blood Coagul Fibrinolysis. 2014 Jan;25(1):77-80
references.pmid: 24231694
references.citation: J Med Case Rep. 2012 Oct 11;6:350
references.pmid: 23057781
references.citation: Int J Hematol. 2015 Apr;101(4):362-8
references.pmid: 25690486