title: Antibodies to factor VIIa in patients with haemophilia and high-responding inhibitors.
abstract: The haemostatic effect of by-passing agents such as activated prothrombin complex concentrates (aPCC) and recombinant factor VIIa is inadequate in some patients with severe haemophilia and high-responding inhibitors. Theoretically, this could be due to antibody reactivity to procoagulant proteins other than the deficient factor. To evaluate this hypothesis, immunoglobulin (Ig) fractions from six multi-transfused patients (three haemophilia A and three haemophilia B) were purified on protein A sepharose and then subjected to immunoaffinity chromatography on factor IX sepharose and factor VIIa sepharose. All three Ig fractions from the haemophilia B patients, but not commercially available Ig, contained antibodies that bound to both gels. None of the haemophilia A patients had antibodies to factor IX but all three had antibodies towards factor VIIa. The immunoaffinity purified antifactor IX and VIIa antibodies from the haemophilia B patients inhibited thrombin formation in vitro using Feiba as active enzyme, but had no significant effect in the presence of NovoSeven. In contrast, no inhibitory effect was observed with the antifactor VIIa antibodies from the haemophilia A patients. Cross-reactivity to factor IX was seen for the antifactor VIIa antibodies from the patients with haemophilia B. Our findings show that antibody reactivity to other procoagulant factors such as factor VIIa exists in patients with high-responding inhibitors and that these antibodies may have an inhibitory potential that correlates to the amount of active enzyme present. The characterization of the antibody profile may facilitate an optimal treatment with by-passing agents in severe bleeding events.
authors.affiliation: Department of Coagulation Disorders, University of Lund, University Hospital, Malmö, Sweden. Jan.astermark@medforsk.mas.lu.se
authors.forename: Jan
authors.initials: J
authors.lastname: Astermark
authors.forename: Maj
authors.initials: M
authors.lastname: Ekman
authors.forename: Erik
authors.initials: E
authors.lastname: Berntorp
mesh_terms: D000906:Antibodies / Q000097:blood* / Q000276:immunology; D019774:Blood Coagulation Factor Inhibitors / Q000378:metabolism*; D015153:Blotting, Western; D002846:Chromatography, Affinity; D015942:Factor VIIa / Q000276:immunology*; D006467:Hemophilia A / Q000097:blood / Q000276:immunology*; D002836:Hemophilia B / Q000097:blood / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D011994:Recombinant Proteins / Q000276:immunology; D013917:Thrombin / Q000378:metabolism
chemical_list: D000906:Antibodies; D019774:Blood Coagulation Factor Inhibitors; D011994:Recombinant Proteins; D015942:Factor VIIa; D013917:Thrombin