title: Diagnostic and prognostic value of factor VIII binding antibodies in acquired hemophilia A: data from the GTH-AH 01/2010 study.
abstract: Essentials Factor VIII (FVIII) binding IgG detected by ELISA could be an alternative to the Bethesda assay. We studied the performance of anti-FVIII IgG ELISA in patients with acquired hemophilia and controls. Anti-FVIII IgG > 99th percentile of controls was highly sensitive and specific. Patients with high anti-FVIII IgG have a lower chance of achieving remission.
  
  
  
  Background Acquired hemophilia A is a severe bleeding disorder that requires fast and accurate diagnosis as it occurs often unexpectedly in previously healthy men and women of every age. The Nijmegen-modified Bethesda assay is the diagnostic reference standard for detecting neutralizing autoantibodies against factor VIII (FVIII), but is not widely available, not ideal for quantifying the complex type 2 inhibitors seen in acquired hemophilia, and suffers from high inter-laboratory variability. Objectives To assess the diagnostic and prognostic value of FVIII-binding antibodies as detected by ELISA compared with the Nijmegen Bethesda assay. Methods Samples from the time of first diagnosis and clinical data were available from 102 patients with acquired hemophilia enrolled in the prospective GTH-AH 01/2010 study. Controls (n = 102) were matched for gender and age. Diagnostic cut-offs were determined by receiver-operator curve analysis. The prognostic value was assessed in 92 of the 102 patients by Cox regression analysis of time to partial remission. Results Anti-FVIII IgG above the 99th percentile (> 15 arbitrary units per mL) revealed high sensitivity and specificity (both 0.99; 95% confidence interval, 0.95-1.0) for diagnosing acquired hemophilia. The likelihood of achieving partial remission was related to anti-FVIII IgG concentration (< 300 arbitrary units, 1.0; 300-1050, 0.65; > 1050, 0.39). The Bethesda titer was only associated with the likelihood of partial remission when analyzed in the central laboratory, but not when data from local GTH study sites were used. Conclusion Although the Nijmegen-modified Bethesda assay is the reference standard for demonstrating neutralizing antibodies, the detection of FVIII-binding antibodies by ELISA is similarly sensitive and specific for diagnosing acquired hemophilia. In addition, anti-FVIII IgG may provide prognostic information.
authors.affiliation: Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Werwitzke
authors.affiliation: Institute for Clinical Chemistry and Laboratory Medicine, Freiburg University Hospital, Freiburg, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Geisen
authors.affiliation: Clinical Chemistry, University Medical Center Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Nowak-Göttl
authors.affiliation: Clinical Hemostaseology and Transfusion Medicine, Saarland University Hospital, Homburg/Saar, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Eichler
authors.affiliation: Clinical Hemostaseology and Transfusion Medicine, Saarland University Hospital, Homburg/Saar, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Stephan
authors.affiliation: Center of Coagulation Disorders, Leipzig, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Scholz
authors.affiliation: Hematology and Oncology, University Hospital Eppendorf, Hamburg, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Holstein
authors.affiliation: Internal Medicine, Vivantes Clinic Friedrichshain, Berlin, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Klamroth
authors.affiliation: Hematology and Hemostasis, Vienna Medical University, Vienna, Austria.
authors.forename: P
authors.initials: P
authors.lastname: Knöbl
authors.affiliation: Hemophilia Care Center, SRH Kurpfalzkrankenhaus Heidelberg, Heidelberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Huth-Kühne
authors.affiliation: Hemostasis, Hemotherapy, and Transfusion Medicine, Heinrich Heine University Center Medical Center, Düsseldorf, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Bomke
authors.affiliation: Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Tiede
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D001780:Blood Coagulation Tests; D004797:Enzyme-Linked Immunosorbent Assay; D005169:Factor VIII / Q000276:immunology*; D005260:Female; D006467:Hemophilia A / Q000097:blood* / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012372:ROC Curve; D012074:Remission Induction; D012680:Sensitivity and Specificity; D055815:Young Adult
chemical_list: D007074:Immunoglobulin G; C078147:F8 protein, human; D005169:Factor VIII
keywords: ELISA; antibodies; factor VIII; hemophilia A, acquired; inhibitors