title: Characteristics of hemophilia patients with factor VIII inhibitors detected by prospective screening.
abstract: Characteristics of inhibitors identified by prospective screening may differ from those detected clinically. In a prospective study at 17 hemophilia centers with central inhibitor measurement by Nijmegen-Bethesda assay, 23 (2.8%) of 824 hemophilia A patients had new inhibitors detected: nine high-titer inhibitors (HTI: 7 ≥ 5.0 NBU plus 2 of 2.6 and 3.4 NBU at immune tolerance induction initiation) and 14 low-titer inhibitors (LTI: 0.5-1.9 NBU). HTI occurred at an earlier age (median 2 years, range 1-18, vs. median 11 years, range 2-61, P = 0.016). Both HTI (22%) and LTI (43%) occurred in non-severe patients. All HTI, but only 64% of LTI, were found to be FVIII-specific by chromogenic Bethesda assay or fluorescence immunoassay (FLI), indicating a high rate of false-positive LTI. Repeat specimens confirmed all HTI, 7/9 LTI, and 7/7 FVIII-specific LTI. FLI results were similar between HTI and FVIII-specific LTI; all included IgG1 and IgG4 subclasses. A comparable prospective study conducted from 1975 to 1979 at 13 U.S. centers found 31 (2.4%) new inhibitors among 1,306 patients. In both studies, one-third of inhibitors occurred in non-severe patients and one-quarter after 150 exposure days (ED). Significant differences were seen in the age at which inhibitors occurred (median 16 years in the older study vs. 5 years currently, P = 0.024) and in ED before inhibitor development, 10% in the older study and 43% currently study occurring within 20 ED, suggesting a temporal change in inhibitor development. Prospective screening detects inhibitors in patients of all severities, ages, and ED. Some LTI, however, are false positives.
authors.affiliation: Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia.
authors.forename: Connie H
authors.initials: CH
authors.lastname: Miller
authors.affiliation: Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia.
authors.forename: Anne S
authors.initials: AS
authors.lastname: Rice
authors.affiliation: Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia.
authors.forename: Brian
authors.initials: B
authors.lastname: Boylan
authors.affiliation: Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia.
authors.forename: Amanda B
authors.initials: AB
authors.lastname: Payne
authors.affiliation: Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia.
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Kelly
authors.affiliation: Gulf States Hemophilia and Thrombophilia Center, Houston, Texas.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Escobar
authors.affiliation: Comprehensive Center for Bleeding Disorders, Blood Center of Wisconsin and Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Joan
authors.initials: J
authors.lastname: Gill
authors.affiliation: Louisiana Center for Bleeding and Clotting Disorders, New Orleans, Louisiana.
authors.forename: Cindy
authors.initials: C
authors.lastname: Leissinger
authors.affiliation: Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia.
authors.forename: J Michael
authors.initials: JM
authors.lastname: Soucie
mesh_terms: D000293:Adolescent; D000328:Adult; D001323:Autoantibodies / Q000097:blood*; D019774:Blood Coagulation Factor Inhibitors / Q000097:blood*; D002648:Child; D002675:Child, Preschool; D005169:Factor VIII / Q000037:antagonists & inhibitors*; D005260:Female; D006467:Hemophilia A / Q000097:blood*; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood*; D007223:Infant; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies
chemical_list: D001323:Autoantibodies; D019774:Blood Coagulation Factor Inhibitors; D007074:Immunoglobulin G; C078147:F8 protein, human; D005169:Factor VIII