Characteristics, Mechanisms of Action, and Epitope Mapping of Anti-factor VIII Antibodies

Lavigne-Lissalde, Géraldine; Rothschild, Chantal; Pouplard, Claire; Lapalud, Priscilla; Gruel, Yves; Schved, Jean‐François; Granier, Claude

doi:10.1007/s12016-009-8119-0

Cited by 24 publications

(25 citation statements)

References 74 publications

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“…The results are shown in Table 1 for 25 subjects from CHU Sainte-Justine (subjects 1-25) and Table 2 for 7 subjects [26][27][28][29][30][31][32]. fVIII antigen concentration and activity were determined as previously reported.…”

Section: Results Fviii Antigen Concentration and Activity In Hemophilmentioning

confidence: 99%

“…1 Five of the 7 subjects (subjects 26-30) were found to be anti-fVIII Ab positive, as listed in Table 2. Four subjects (26,27,28, and 31) were followed through 5 cycles of therapy with 5 different fVIII concentrates (products A-E) accompanied by the determination of fVIII antigen concentration, fVIII activity, and anti-fVIII Ab. Three subjects (29,30, and 32) were studied through 3 cycles of therapeutic intervention with the same product (B).…”

Section: Analyses Of Inhibitor-free Hemophilia a Human Plasma In Flimentioning

confidence: 99%

“…Immunoassays have been used to detect anti-fVIII antibodies, but report only the presence of antibody relative to controls or quantitation based on recombinant constructs as calibrators. [27][28][29][30][31][32][33][34] An assay for the detection of such antibodies with a suitable calibrator for absolute quantitation has been unavailable.…”

Section: Introductionmentioning

confidence: 99%

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Quantitation of anti–factor VIII antibodies in human plasma

Krudysz-Amblo

Parhami-Seren

Butenas

et al. 2009

Blood

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The presence of antibodies (Abs) in hemophilia A patients can potentially influence the therapeutic qualities of factor VIII (fVIII) administration. Much work has been focused on the presence of inhibitory antibodies, whereas the quantitation of noninhibitory anti-fVIII antibodies has been largely undetermined. Our objective was to develop a sensitive and specific fluorescencebased immunoassay (FLI) for the quantitation of anti-fVIIIAbs in human plasma. Affinity-purified human anti-fVIIIAb, isolated from a hemophilia A subject, was used as a calibrator with a detectability limit of 40 (؎1.5) pM. The calibrator and the human plasma anti-fVIIIAb were captured on recombinant fVIII (rfVIII)-coupled microspheres and probed with mouse anti-human Ig-R-phycoerythrin. Plasma samples from 150 healthy donors and 39 inhibitor-negative hemophilia A subjects were compared with 4 inhibitor-positive hemophilia A plasma samples with inhibitor titers of 1 BU/mL (94.6 ؎ 0.8 nM), 11 BU/mL (214.3 ؎ 7.1 nM), 106 BU/mL (2209.4 ؎ 84.9 nM), 140 BU/mL (2417.7 ؎ 3.8 nM) as measured by the Nijmegen method. We also describe the validation of a mouse anti-human fVIIIAb as a surrogate calibrator. Four healthy individuals (3%) showed detectable antifVIIIAb in the range of 0.6 to 6.2 nM, whereas 13 (33%) of the 39 inhibitor-free hemophilia A subjects were positive for anti-fVIIIAb in the range of 0.5 to 20 nM. The method may be useful for therapeutic management of hemophilia A patients.

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Section: Results Fviii Antigen Concentration and Activity In Hemophilmentioning

confidence: 99%

Section: Analyses Of Inhibitor-free Hemophilia a Human Plasma In Flimentioning

confidence: 99%

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Quantitation of anti–factor VIII antibodies in human plasma

Krudysz-Amblo

Parhami-Seren

Butenas

et al. 2009

Blood

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“…Antibodies against FVIII may either block the function of FVIII or promote the clearance of factor VIII from circulation [8, 9]. Identification of the FVIII epitopes to which inhibitor antibodies bind is crucial for understanding the mechanisms of inhibitor activity [9].…”

Section: Introductionmentioning

confidence: 99%

Characterization of anti-factor VIII antibody in a patient with acquired hemophilia A

Lim

Jang

et al. 2013

Blood Res

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Acquired hemophilia A (AHA) is a bleeding disorder caused by the development of an auto-antibody against endogenous factor VIII (FVIII). In this study, the epitope of the autoantibody was identified in a 67-year-old female patient with AHA. A prolonged activated partial thromboplastin time (77.4 s) that failed to correct in an incubation mixing test (68.2 s), a decreased FVIII activity, and a high FVIII inhibitor (14.6 Bethesda units/mL) were observed. Enzyme-linked immunosorbent assay demonstrated that the antibody belonged to the immunoglobulin G4 subclass. An immunoblotting assay revealed the light chain (A3/C1/C2 domain) of FVIII as the binding region of the antibody. The bleeding experienced by our patient resulted from the interference of FVIII binding to both FIX by anti-A3 antibodies and phospholipids and von Willebrand factor by anti-C2 antibodies. To the best of our knowledge, this is the first study in Korea characterizing an autoantibody in the context of AHA.

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“…Epitope mapping of inhibitors has been the subject of intense research. Two leaders in the area have summarized the current literature and their observations on epitope mapping: Lavigne-Lissalde and her colleagues have presented the most recent findings on the isotypes, kinetic properties, and mechanism of action of anti-FVIII Abs [1]. The authors also describe a novel approach that is likely to facilitate the monitoring of changes in the epitope specificity FVIII inhibitors.…”

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confidence: 99%

Anti-factor VIII Antibodies (Inhibitors) in Hemophilia A: In Dire Need of Basic and Therapeutic Research

Kaveri

2009

Clinic Rev Allerg Immunol

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Hemophilia A, a congenital, severe bleeding disorder, is caused by the absence or functional abnormality of factor VIII (FVIII) that occurs with a frequency of about one in 5,000 boys. FVIII is produced in the liver, and minute amounts of which (0.2 μg/ml plasma) ensure an efficient coagulation. Abnormalities in the gene encoding FVIII lead to the deficiency of FVIII or production of a functionally defective molecule. Therefore, substituting the FVIII molecule represents the treatment of choice during bleeding incidences in hemophilia patients. Thus, most hemophilia patients require regular supplementation with intravenously administered recombinant or plasma-derived FVIII. About 25-40% of the hemophilia A patients who receive FVIII develop antibodies against the infused FVIII. These anti-FVIII alloantibodies are called "inhibitors."FVIII inhibitors neutralize the infused FVIII, thus exposing the patients to an extremely precarious situation and a serious challenge to the clinicians, as subsequent treatment options become extremely limited. Immune tolerance induction is the currently practiced approach to eradicate inhibitors, to restore replacement FVIII pharmacokinetics, and to improve bleeding management and thereby the quality of life. However, the exorbitant cost involved in this therapy has a direct bearing on the socioeconomic issues. With the emergence of the state-ofthe-art methods for elimination of contaminants and rapidly improving production processes that have ensured the safety of the products and the absence of contamination with blood-borne agents such as HIV, hepatitis, and prions, the risk of developing FVIII inhibitors poses a major and almost the only most serious complication in the treatment of hemophilia A patients. FVIII inhibitors have therefore been subject to extensive investigation by several groups of researchers over the last two decades. Although the basic characteristics and the mode of action of inhibitors have been well documented, issues on the nature of risk factors that predispose a patient for the development of inhibitors have remained a subject of debate. Designing appropriate therapeutic strategies to prevent the emergence and to eradicate the anti-FVIII antibodies is the most important concern. A thorough knowledge on the predisposing factors and a careful dissection of both cellular and molecular events leading to the development of inhibitors are important prerequisites in the conception of preventive and therapeutic measures. With this perspective, in this issue of Clinical Reviews in Allergy and Immunology, we have gathered the current views from experts who have contributed significantly on various aspects of FVIII inhibitor development. The authors provide an in depth assessment of diverse topics ranging from risk factors that predispose the hemophilia patients for the development of inhibitors to the conception of novel immunointervention strategies to combat the occurrence of FVIII inhibitors.

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Characteristics, Mechanisms of Action, and Epitope Mapping of Anti-factor VIII Antibodies

Cited by 24 publications

References 74 publications

Quantitation of anti–factor VIII antibodies in human plasma

Quantitation of anti–factor VIII antibodies in human plasma

Characterization of anti-factor VIII antibody in a patient with acquired hemophilia A

Anti-factor VIII Antibodies (Inhibitors) in Hemophilia A: In Dire Need of Basic and Therapeutic Research

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