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Thromb Haemost 2009; 101(05): 834-839
DOI: 10.1160/TH08-08-0508
DOI: 10.1160/TH08-08-0508
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Epitope specificity of anti-factor VIII antibodies from inhibitor positive acquired and congenital haemophilia A patients using synthetic peptides spanning A and C domains
Financial support: This study was supported by a grant from Tehran University of Medical Sciences (to FS) and the National Heart Lung and Blood Institute grants HL61922 and HL65578 (to B.M.C.-F.).
Further Information
Publication History
Received:
16 August 2008
Accepted after major revision:
28 January 2009
Publication Date:
24 November 2017 (online)
Summary
Development of antibodies (Ab) that either block the function of coagulation factor VIII (FVIII) (inhibitors) or clear it from circulation, seriously complicate the treatment of haemophilia A patients with FVIII products. Autoantibodies which develop in subjects without congenital FVIII defects, cause acquired haemophilia, a rare but life-threatening coagulopathy. Identification of the FVIII epitopes to which inhibitor Abs bind will help understanding the mechanisms of inhibitor activity, and perhaps development of new therapies. Here, we examined the FVIII peptide sequence regions recognised by anti-FVIII Ab in the plasma of six congenital and one acquired haemophilia patients with high inhibitor titers (24.4–2000 BU/ml). We used indirect ELISA and overlapping synthetic peptides, 20 residues long, spanning the sequence of the A and C FVIII domains. None of the plasma samples reacted with A1, A3 or C1 domain peptides. Six plasmas reacted with A2 and/or C2 peptides. Peptides spanning residues A2–521–690 and C2–2251–2332 were recognised most frequently and strongly. They include residues that contribute to the binding sites for activated factor IX and phosphatidyl serine/ von Willebrand factor. These results suggest that anti-FVIII Abs share a pattern of antigen specificity in our panel of patients, and that exposed regions of the FVIII molecule that form functionally important binding sites elicit an intense Ab response.
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