title: Risk factors for inhibitor formation in haemophilia: a prevalent case-control study.
abstract: Inhibitor formation is a major complication of haemophilia treatment. In a prevalent case-control study, we evaluated blood product exposure, genotype and HLA type on haemophilia A inhibitor formation. Product exposure was extracted from medical records. Genotype was determined on stored DNA samples by detection of virtually all mutations-SSCP (DOVAM-S) and subcycling PCR. HLA typing was performed by PCR amplification and exonuclease-released fluorescence. Cases experienced higher intensity factor, 455 vs. 200 U per exposure, P < 0.005, more frequent central nervous system (CNS) bleeding, seven of 20 (35.0%) vs. one of 57 (1.7%), P = 0.001 and more commonly from inhibitor families, seven of 20 (35.0%) vs. zero of 57 (0%), P < 0.001, and African-American, 12 of 63 (19.0%) vs. six of 117 (5.1%), P = 0.015. Among the latter, CNS bleeding was more commonly the initial bleed, 60% vs. 0%, P < 0.001, and survival was shorter, 14 vs. 38 yr, P = 0.025. Inhibitor formation was uncommon in those with missense mutations, two of 65 (3.1%) vs. 31 of 119 (26.0%), P = 0.008, and unrelated to factor VIII immunogenic epitope, P = 0.388, or HLA type, P > 0.100. Genotype was not associated with race. Time to immune tolerance was shorter for titres <120 vs. > or = 120 BU/mL, six vs. 16 months, P < 0.01, but unaffected by tolerizing dose regimen, P > 0.50. Inhibitor formation is associated with high intensity product exposure, CNS bleeding, African-American race and low frequency of missense mutations. The ideal time to initiate prophylaxis to reduce CNS bleeding and inhibitor formation will require prospective studies.
authors: Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213-4306, USA. ragni@pitt.edu
authors: M V
authors: MV
authors: Ragni
authors: O
authors: O
authors: Ojeifo
authors: J
authors: J
authors: Feng
authors: J
authors: J
authors: Yan
authors: K A
authors: KA
authors: Hill
authors: S S
authors: SS
authors: Sommer
authors: M N
authors: MN
authors: Trucco
authors: D J
authors: DJ
authors: Brambilla
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000925:Anticoagulants / Q000276:immunology* / Q000627:therapeutic use; D019774:Blood Coagulation Factor Inhibitors / Q000235:genetics / Q000276:immunology*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005838:Genotype; D006467:Hemophilia A / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007223:Infant; D008297:Male; D015995:Prevalence; D012307:Risk Factors; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D019774:Blood Coagulation Factor Inhibitors