title: Inhibitor development in previously untreated patients with hemophilia A: a prospective long-term follow-up comparing plasma-derived and recombinant products.
abstract: In order to assess inhibitor development in previously untreated patients (PUPs) with severe (factor VIII [FVIII]<1%) and moderate (FVIII 1 to 5%) hemophilia A, a prospective study was initiated in 1976. During the 23-year study period, 72 hemophiliacs were frequently exposed prophylactically or on demand to plasma-derived (pd) (n = 51) or recombinant FVIII (rFVIII) (n = 21) concentrates (median 270 exposure days [ED]). Inhibitor testing was performed before the first exposure and at regular intervals thereafter. Of the 72 hemophilia A patients, 22 (32%) developed an inhibitor after 15 ED in median (range 4 to 195); 17 (77%) were high responders (>5 Bethesda Units [BU]), and the remaining 5 patients (23%) were low responders (>0.6 to 5 BU). The severely affected patients (n = 46) showed a significantly higher frequency of inhibitor formation (43%) than did the moderate ones (8%). Comparing the severely affected patients receiving pd products exclusively (n = 35) with those treated with recombinant concentrate (n = 11), 37% of the pd group developed a high-titer inhibitor (>5 BU, median 290 ED in noninhibitor patients) and 36% of the recombinant group (median 49 ED in the noninhibitor patients). However, the exposure status of the recombinant noninhibitor patients is rather low and therefore remains a high risk of developing further inhibitors in the future. The mutation type profile revealed no difference between the pd- and the recombinant-treated patients.
authors.affiliation: The Centre of Pediatrics III, Department of Hematology and Oncology, Johann-Wolfgang-Goethe-University Hospital, Frankfurt am Main and the Institute of Human Genetics (J. Oldenburg) University, Würzburg, Germany. carmen.escuriola@kgu.de
authors.forename: Wolfhart
authors.initials: W
authors.lastname: Kreuz
authors.forename: Carmen Escuriola
authors.initials: CE
authors.lastname: Ettingshausen
authors.forename: Alex
authors.initials: A
authors.lastname: Zyschka
authors.forename: Johannes
authors.initials: J
authors.lastname: Oldenburg
authors.forename: Inmaculada Martinez
authors.initials: IM
authors.lastname: Saguer
authors.forename: Silke
authors.initials: S
authors.lastname: Ehrenforth
authors.forename: Thomas
authors.initials: T
authors.lastname: Klingebiel
mesh_terms: D001323:Autoantibodies / Q000097:blood*; D015331:Cohort Studies; D005169:Factor VIII / Q000008:administration & dosage / Q000276:immunology*; D005500:Follow-Up Studies; D006467:Hemophilia A / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D002836:Hemophilia B / Q000188:drug therapy / Q000235:genetics / Q000276:immunology; D006801:Humans; D009154:Mutation; D011446:Prospective Studies; D011994:Recombinant Proteins / Q000276:immunology*; D012306:Risk; D013997:Time Factors
chemical_list: D001323:Autoantibodies; D011994:Recombinant Proteins; C078147:F8 protein, human; D005169:Factor VIII