title: Natural history and clinical characteristics of inhibitors in previously treated haemophilia A patients: a case series.
abstract: BACKGROUND
  Development of inhibitors is the most serious complication in haemophilia A treatment. The assessment of risk for inhibitor formation in new or modified factor concentrates is traditionally performed in previously treated patients (PTPs). However, evidence on risk factors for and natural history of inhibitors has been generated mostly in previously untreated patients (PUPs). The purpose of this study was to examine cases of de novo inhibitors in PTPs reported in the scientific literature and to the EUropean HAemophilia Safety Surveillance (EUHASS) programme, and explore determinants and course of inhibitor development.
  
  
  METHODS
  We used a case series study design and developed a case report form to collect patient level data; including detection, inhibitor course, treatment, factor VIII products used and events that may trigger inhibitor development (surgery, vaccination, immune disorders, malignancy, product switch).
  
  
  RESULTS
  We identified 19 publications that reported 38 inhibitor cases and 45 cases from 31 EUHASS centres. Individual patient data were collected for 55/83 (66%) inhibitor cases out of 12 330 patients. The median (range) peak inhibitor titre was 4.4 (0.5-135.0), the proportion of transient inhibitors was 33% and only two cases of 12 undergoing immune tolerance induction failed this treatment. In the two months before inhibitor development, surgery was reported in nine (22%) cases, and high intensity treatment periods reported in seven (17%) cases.
  
  
  CONCLUSIONS
  By studying the largest cohort of inhibitor development in PTPs assembled to date, we showed that inhibitor development in PTPs, is on average, a milder event than in PUPs.
authors.affiliation: Department of Clinical Epidemiology and Biostastics, McMaster University, Hamilton, ON, Canada.
authors.forename: A
authors.identifier: http://orcid.org/0000-0002-3331-8766
authors.initials: A
authors.lastname: Iorio
authors.affiliation: Department of Clinical Epidemiology and Biostastics, McMaster University, Hamilton, ON, Canada.
authors.forename: A M
authors.initials: AM
authors.lastname: Barbara
authors.affiliation: Department of Infection, Immunity & Cardiovascular Disease, University of Sheffield, Sheffield, UK.
authors.forename: M
authors.initials: M
authors.lastname: Makris
authors.affiliation: Van Creveldkliniek University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: K
authors.initials: K
authors.lastname: Fischer
authors.affiliation: San Bortolo Hospital, Vicenza, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Castaman
authors.affiliation: Congenital Coagulopathies Centre, Santa Maria Hospital, Lisbon, Portugal.
authors.forename: C
authors.initials: C
authors.lastname: Catarino
authors.affiliation: Department of Infection, Immunity & Cardiovascular Disease, University of Sheffield, Sheffield, UK.
authors.forename: E
authors.initials: E
authors.lastname: Gilman
authors.affiliation: Department of Pediatric Hematology, Ege University Children's Hospital, Izmir, Turkey.
authors.forename: K
authors.initials: K
authors.lastname: Kavakli
authors.affiliation: Centre de traitement des Hemophiles de Bicetre, Paris, France.
authors.forename: T
authors.initials: T
authors.lastname: Lambert
authors.affiliation: Department of Hematology, Cancer Center, Helsinki University Hospital, Helsinki, Finland.
authors.forename: R
authors.initials: R
authors.lastname: Lassila
authors.affiliation: Haematology Hospital "Joan Pavel", Sofia, Bulgaria.
authors.forename: T
authors.initials: T
authors.lastname: Lissitchkov
authors.affiliation: Van Creveldkliniek University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Mauser-Bunschoten
authors.affiliation: Regional University Hospital of Málaga, Málaga, Spain.
authors.forename: M E
authors.initials: ME
authors.lastname: Mingot-Castellano
authors.affiliation: Istanbul University Haemophilia Centre, Istanbul, Turkey.
authors.forename: N
authors.initials: N
authors.lastname: Ozdemir
authors.affiliation: Department of Medicine I, Haemophilia Centre, Medical University of Vienna, Vienna, Austria.
authors.forename: I
authors.initials: I
authors.lastname: Pabinger
authors.affiliation: Hospital Vall d'Hebron, Barcelona, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Parra
authors.affiliation: Barts and the London School of Medicine, London, UK.
authors.forename: J
authors.initials: J
authors.lastname: Pasi
authors.affiliation: Haemophilia Center, Universitaire Ziekenhuis Gasthuisberg, Leuven, Belgium.
authors.forename: K
authors.initials: K
authors.lastname: Peerlinck
authors.affiliation: Département d'Hématologie Transfusion, Centre Hospitalier Régional Universitaire de Lille, Lille, France.
authors.forename: A
authors.initials: A
authors.lastname: Rauch
authors.affiliation: Regional Reference Centre for Inherited Bleeding Disorders, University Hospital of Parma, Parma, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Roussel-Robert
authors.affiliation: Hôpital Cochin, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Serban
authors.affiliation: European Haemophilia Center, Paediatric Clinical Emergency Hospital Louis Turcanu, Timisoara, Romania.
authors.forename: A
authors.initials: A
authors.lastname: Tagliaferri
authors.affiliation: Department of Disorders of Haemostasis and Internal Medicine, Institute of Haematology & Transfusion Medicine, Warsaw, Poland.
authors.forename: J
authors.initials: J
authors.lastname: Windyga
authors.affiliation: Haemophilia Centre, Azienda Universitaria Ospedaliera di Padova, Padova, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Zanon
mesh_terms: D000328:Adult; D006467:Hemophilia A / Q000188:drug therapy; D006801:Humans; D008875:Middle Aged; D019021:Natural History / Q000379:methods*; D012307:Risk Factors
keywords: factor VIII inhibitors; haemophilia A; previously treated patients