Characterization of antibodies to factor VIII in hemophilia A patients treated by immune tolerance therapy.
The treatment of hemophilia A patients has improved in this decade by production of recombinant factor VIII (FVIII) in mammalian cells, which has significantly reduced contamination by infectious agents. A remaining serious problem in 25-30% of patients with severe hemophilia A is the appearance of antibodies that inactivate FVIII. The present therapy for this condition is frequent treatment with high doses of FVIII to induce tolerance, which is defined as a negative Bethesda assay. Serial plasma samples from 50 evaluable patients in a large study of 72 previously untreated patients were tested to determine whether tolerized patients have actually lost all their anti-FVIII by using a 10 fold more sensitive immunoprecipitation (IP) method of measuring all anti-FVIII antibodies. Six of the 22 patients with inhibitors were given tolerance therapy, and 3 of them were only partially tolerized as determined by IP assay. Seven patients with 1-11 BU/mL lost their inhibitor spontaneously, while 5 non-inhibitor patients with low level immune responses similarly became antibody negative. In a smaller study, a tolerized patient with 0 BU/mL had remaining non-inhibitory antibody levels high enough to reduce the FVIII half-life significantly. Plasmas from 2 patients who were not tolerized, were tested by the IP assay for the A2 and/or C2 domain specificity of the anti-FVIII over time. The antibodies detected were directed against both the heavy and light chains of FVIII, and they increased and decreased at the same rate before and during tolerance therapy.
Scandella
D
D
American Red Cross, Holland Laboratory, Rockville, MD 20855, USA.
Reyes
H
H
Felch
M
M
Sakurai
Y
Y
D000918:Antibody Specificity; D005169:Factor VIII / Q000008:administration & dosage / Q000276:immunology*; D006467:Hemophilia A / Q000150:complications / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D016056:Immunodominant Epitopes; D007518:Isoantibodies / Q000097:blood*; D011233:Precipitin Tests
D016056:Immunodominant Epitopes; D007518:Isoantibodies; D005169:Factor VIII