Cases reported "Hemophilia A"

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1/4. Human antibodies with specificity for the C2 domain of factor viii are derived from VH1 germline genes.

    A serious complication in hemophilia care is the development of factor viii (FVIII) neutralizing antibodies (inhibitors). The authors used V gene phage display technology to define human anti-FVIII antibodies at the molecular level. The IgG4-specific, variable, heavy-chain gene repertoire of a patient with acquired hemophilia was combined with a nonimmune, variable, light-chain gene repertoire for display as single-chain variable domain antibody fragments (scFv) on filamentous phage. ScFv were selected by 4 rounds of panning on immobilized FVIII light chain. sequence analysis revealed that isolated scFv were characterized by V(H) domains encoded by germline genes DP-10, DP-14, and DP-88, all belonging to the V(H)1 gene family. All clones displayed extensive hypermutation and were characterized by unusually long CDR3 sequences of 20 to 23 amino acids. immunoprecipitation revealed that all scFv examined bound to the C2 domain of FVIII. Furthermore, isolated scFv competed with an inhibitory murine monoclonal antibody for binding to the C2 domain. Even though scFv bound FVIII with high affinity, they did not inhibit FVIII activity. Interestingly, the addition of scFv diminished the inhibitory potential of patient-derived antibodies with C2 domain specificity. These results suggest that the epitope of a significant portion of anti-C2 domain antibodies overlaps with that of the scFv isolated in this study. (blood. 2000;95:558-563)
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2/4. Epitope specificity of anti-FVIII antibodies during immune tolerance therapy with factor viii preparation containing von willebrand factor.

    The study aimed at characterizing the putative changes in the epitope specificity of anti-FVIII antibodies during a successful immune tolerance treatment of the haemophilia A patient with the factor viii (FVIII) preparation containing the von willebrand factor (VWF). At the beginning of treatment, anti-FVIII inhibitory antibodies recognizing predominantly the light chain of FVIII were prevalent and persisted throughout the treatment. More detailed characterization of the FVIII antibody epitope specificity by using GST-fusion proteins corresponding to different FVIII domains revealed the prevalence of C1-domain-specific antibodies, while a remarkably lower amount of antibodies were targeted at the C2 and the a3 domains of the FVIII light chain and towards the A2 and the A1 domain of the FVIII heavy chain. The epitope specificity of antibodies remained rather unchanged throughout treatment except the elevated level of C2-domain-specific FVIII antibodies after a temporary interruption of treatment. The patient's antibodies were unable to interfere with the FVIII binding to VWF or to phospholipids, but inhibited FXa generation and the binding of FX to FVIII on the phospholipid monolayer. Thus, a unique pattern of the epitope specificity of FVIII antibodies and the mechanism to inhibit FVIII:C activity by FVIII-light-chain-specific antibodies were characterized.
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ranking = 1.6
keywords = specificity
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3/4. Immunoblot analysis shows changes in factor viii inhibitor chain specificity in factor viii inhibitor patients over time.

    We have used immunoblotting of purified factor viii (FVIII) to determine whether or not changes in FVIII chain specificity occur during the course of an inhibitor. Serial plasma samples from 15 inhibitor patients (13 hemophilic and two spontaneous) were analyzed. Nine of the 15 antibodies, all with epitopes on the 44-kilodalton (Kd) thrombin fragment of the 92-Kd FVIII heavy chain and/or the 72-Kd thrombin fragment of the 80-Kd FVIII light chain, showed no change in FVIII chain specificity. However, six of the inhibitors analyzed showed changes in FVIII fragment specificity. Four inhibitors (three hemophilic and one spontaneous) reactive with 72-Kd thrombin fragment also became reactive with the 44-Kd thrombin fragment after an anamnestic response to FVIII infusion. Another inhibitor with epitopes on both the 54-Kd and 44-Kd thrombin fragments lost most of its reactivity with the 44-Kd fragment but retained its reactivity with the 54-Kd fragment following a FVIII infusion. The inhibitor later regained its 44-Kd-fragment reactivity but lost its 54-Kd-fragment reactivity following treatment with FEIBA, FVIII inhibitor bypassing activity. The last inhibitor studied had an antibody to either the 44-Kd fragment or to both the 44-Kd and 72-Kd fragments during anamnestic responses to FVIII. These data indicate that a FVIII inhibitor patient can potentially produce antibody to multiple areas on the FVIII molecule and that this must be taken into account in the design of specific therapeutic products.
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4/4. Neutralizing antiidiotypic antibodies to factor viii inhibitors after desensitization in patients with hemophilia a.

    hemophilia a patients producing antibodies towards FVIII are usually treated with infusions of high doses of FVIII in an attempt to "desensitize" them. To examine the mechanisms by which such desensitization operates, sequential plasma samples of two unrelated inhibitor patients were analyzed for anti-FVIII and antiidiotypic antibodies before and during infusions of high doses of FVIII. Anti-FVIII antibodies were separated from antiidiotypic antibodies by immunoaffinity chromatography before analysis. We show in the present study that the concentration of anti-FVIII antibodies did not change during a successful desensitization and that antibodies maintained their capacity to inhibit the procoagulant function of FVIII, even though the number of Bethesda units in plasma was reduced to undetectable levels. Using a competition assay with mAbs, we further show that the specificity of human antibodies did not vary significantly during therapy. Finally, we show that the treatment elicited antiidiotypic antibodies, which neutralized the inhibitory capacity of anti-FVIII antibodies. Inhibitor antibodies can therefore not be accurately evaluated in plasma, as their function appears to be neutralized by antiidiotypic antibodies. These findings could have implications for the design of new therapies for hemophilia a patients with inhibitors.
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