title: Recombinant factor concentrates may increase inhibitor development: a single centre cohort study.
abstract: Recent reports have raised concerns regarding potential risk factors for inhibitor development. In Israel, all haemophilia patients (n = 479) are followed by the National Hemophilia Center. Most children are neonatally exposed to factor concentrate (due to circumcision performed at the age of 8 days). The impact of early exposure and recombinant FVIII products (rFVIII) administration (approved in Israel since 1996) upon inhibitor occurrence in our cohort of haemophilia A (HA) patients was analysed. Two hundred ninety-two consecutive paediatric cases with a first symptomatic onset of HA were enrolled and followed over a median time of 7 years [min-max: 9 months to 17 years]. Study endpoint was inhibitor development against factor VIII. In addition, the treatment regimens applied, i.e. bolus administration or 'continuous infusion' and the family history of inhibitor development were investigated. During the follow-up period 31/292 children (10.6%) developed high titre inhibitors. Inhibitors occurred in 14/43 (32.5%) HA patients neonatally exposed to rFVIII, as compared to 22/249 previously treated with Plasma Derived (PD) products (8.8%). The odds ratio for inhibitor formation in rFVIII treated HA patients was 3.43 (95% CI: 1.36-8.65). Transient inhibitor evolved among 2/43 paediatric HA patients, only among those treated with rFVIII. The risk of inhibitor detection significantly increased among HA children treated by continuous infusion (P = 0.025). Our experience shows that the risk of inhibitor formation may be increased by early exposure to recombinant concentrates. The multiple variables affecting inhibitor incidence deserve further attention by larger prospective studies.
authors.affiliation: The Israeli National Hemophilia Center, Tel Hashomer Sackler Medical School, Tel Aviv University, Tel Aviv, Israel.
authors.forename: T
authors.initials: T
authors.lastname: Strauss
authors.forename: A
authors.initials: A
authors.lastname: Lubetsky
authors.forename: B
authors.initials: B
authors.lastname: Ravid
authors.forename: D
authors.initials: D
authors.lastname: Bashari
authors.forename: J
authors.initials: J
authors.lastname: Luboshitz
authors.forename: S
authors.initials: S
authors.lastname: Lalezari
authors.forename: M
authors.initials: M
authors.lastname: Misgav
authors.forename: U
authors.initials: U
authors.lastname: Martinowitz
authors.forename: G
authors.initials: G
authors.lastname: Kenet
mesh_terms: D000293:Adolescent; D001323:Autoantibodies / Q000097:blood*; D019774:Blood Coagulation Factor Inhibitors / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005169:Factor VIII / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D006467:Hemophilia A / Q000188:drug therapy* / Q000276:immunology*; D006801:Humans; D007223:Infant; D007557:Israel; D008297:Male; D011994:Recombinant Proteins / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D001323:Autoantibodies; D019774:Blood Coagulation Factor Inhibitors; D011994:Recombinant Proteins; D005169:Factor VIII