Non‐neutralizing anti‐FVIII antibodies: different binding specificity to different recombinant FVIII concentrates

Vincent, A; Lillicrap, David; Boulanger, A.; Meilleur, Courtney E.; Amesse, Claudine; St‐Louis, Jean; Rivard, Georges E.

doi:10.1111/j.1365-2516.2008.01909.x

Cited by 16 publications

(25 citation statements)

References 5 publications

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“…13 On the other hand, results presented by Vincent et al found antibody specificities directed against only the B-domain. 40 Our own data presented in this study seem to confirm the results reported by Vincent et al, although we did identify 1 of 600 healthy individuals with FVIII-binding antibody titers Ն 1:80 that recognized both fulllength FVIII and BDD FVIII.…”

Section: Discussionsupporting

confidence: 91%

“…12,13,39 Another study which used an ELISA-based approach found a prevalence of 12% (6 of 49). 40 In contrast to our study which only included patients with severe hemophilia A (FVIII activity Ͻ 1%), the studies presented by Krudysz-Amblo et al, Lebreton et al, and Zakarija et al included patients with all severities of hemophilia A. 12,13,39 We believe that discrepancies in results for the prevalence of FVIII-binding antibodies between the various studies might be because of differences in the patient populations investigated and different assay formats.…”

Section: Discussionmentioning

confidence: 62%

See 1 more Smart Citation

Distinct characteristics of antibody responses against factor VIII in healthy individuals and in different cohorts of hemophilia A patients

Whelan

Hofbauer

Horling

et al. 2013

Blood

165

200

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 62%

Distinct characteristics of antibody responses against factor VIII in healthy individuals and in different cohorts of hemophilia A patients

Whelan

Hofbauer

Horling

et al. 2013

Blood

165

200

View full text Add to dashboard Cite

“…[13][14][15][16][17][18][19][20][21][22]24,25,29,30 Several factors, particularly that all previous studies predominantly included patients with multiple transfusions, explain this large variation and the gaps in knowledge about their potential clinical role. For instance, the intron 22 inversion of FVIII mutation was associated with an increased frequency of NNAs in patients who had had multiple transfusions in 1 study 29 that was not confirmed in another study.…”

Section: Discussionmentioning

confidence: 99%

“…Their prevalence is approximately 2% to 3% in healthy individuals, 16,18,21,24 but estimates in patients who have hemophilia with different degrees of severity vary widely from 12% to 54%. [13][14][15][16][17][18][19][20][21][22]24,25,[29][30][31] Although NNAs and inhibitors cannot be distinguished on the basis of their isotypes, clonality, and epitopes, 32 recent data published by Hofbauer et al 16 indicate that anti-FVIII immunoglobulin G (IgG) with inhibitory activity has an up to 100-fold higher affinity for FVIII than IgG without inhibitory activity. On the basis of cross-reactivity studies, it has also been suggested that FVIII inhibitors in hemophilia A patients originate from the expansion of a natural anti-FVIII clone of B lymphocytes that exists before any treatment with FVIII and secretes anti-FVIII antibodies similar to the natural antibodies found in healthy individuals.…”

Section: Introductionmentioning

confidence: 99%

Nonneutralizing antibodies against factor VIII and risk of inhibitor development in severe hemophilia A

Cannavó

Valsecchi

Garagiola

et al. 2017

Blood

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Key Points• Nonneutralizing antibodies against FVIII are detected in untreated or minimally treated patients with hemophilia A.• The presence of nonneutralizing antibodies is associated with a substantially increased risk of inhibitor development.The development of anti-factor VIII (FVIII) neutralizing antibodies (inhibitors) is the major complication in hemophilia A. Nonneutralizing antibodies (NNAs) have been detected in hemophilia patients and also in unaffected individuals. The aim of this study was to assess the prevalence of NNAs and to evaluate whether their presence is associated with the development of inhibitors in a cohort of previously untreated or minimally treated patients with hemophilia A; plasma samples of 237 patients with severe hemophilia A enrolled in the SIPPET trial were collected before any exposure to FVIII concentrates and analyzed for the presence of anti-FVIII NNAs. Patients were observed for the development of neutralizing antibodies. NNAs were found in 18 (7.6%) of 237 patients at screening, and there was a clear age gradient. Of those with NNAs, 7 patients subsequently developed an inhibitor for a cumulative incidence of 45.4% (95% confidence interval [CI], 19.5% to 71.3%); among the 219 patients without NNAs, 64 (29%) developed an inhibitor (cumulative incidence, 34.0%; 95% CI, 27.1%-40.9%). In Cox regression analyses, patients with NNAs at screening had an 83% higher incidence of inhibitor development than patients without NNAs (hazard ratio [HR], 1.83; 95% CI, 0.84-3.99). For high-titer inhibitors, the incidence rate had an almost threefold increase (HR, 2.74; 95% CI, 1.23-6.12). These associations did not materially change after adjustment. The presence of anti-FVIII NNAs in patients with severe hemophilia A who were not previously exposed to FVIII concentrates is associated with an increased incidence of inhibitors. (Blood. 2017;129(10):1245-1250

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“…Non‐neutralizing anti‐FVIII antibodies (NNA) have been explored in a number of cohorts of patients with haemophilia A. The prevalence has varied, ranging from 12·2% to 53·8% in ELISA‐based studies (Dazzi et al , ; Vianello et al , ; Ling et al , ; Vincent et al , ). We have previously reported a NNA prevalence of 18·9% in inhibitor‐negative subjects in a large cohort of brothers with severe haemophilia A (Klintman et al , ), similar to that observed in a recently described French cohort (Lebreton et al , ).…”

Section: Discussionmentioning

confidence: 99%

Long‐term anti‐FVIII antibody response in Bethesda‐negative haemophilia A patients receiving continuous replacement therapy

Klintman¹,

Hillarp

Berntorp³

et al. 2013

Br J Haematol

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SummaryIt has previously been shown that patients with haemophilia A may develop non-neutralizing anti-factor VIII (FVIII) antibodies (NNA) that escape detection by the Bethesda assay, but are detected using immunebased assays. We and others found NNAs to be directed not only towards non-functional parts of the protein, but towards all regions of the FVIII protein. We also showed a heterogeneous antibody response towards different FVIII products. However, the clinical relevance and the natural history of NNA remain unclear. Therefore, we followed a cohort of unrelated subjects with haemophilia A for 4 years with the goal of exploring the longterm development of NNA using an enzyme-linked immunosorbent assay (ELISA). Ten of 78 subjects (12Á8%) exhibited an immune response that was transient and heterogeneous, and none of the subjects developed an FVIII inhibitor. The result of the ELISA was examined in relation to clinical variables and no significant associations between a positive ELISA and age, F8 mutation, port-a-cath implantation and HCV infection were shown. Interestingly, patients with NNA had significantly fewer bleeding episodes (P = 0Á048) compared with NNA-negative subjects. The results indicate that the immune response to FVIII products within an individual may vary over time. However, the clinical impact of NNA remains unclear.

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Non‐neutralizing anti‐FVIII antibodies: different binding specificity to different recombinant FVIII concentrates

Cited by 16 publications

References 5 publications

Distinct characteristics of antibody responses against factor VIII in healthy individuals and in different cohorts of hemophilia A patients

Distinct characteristics of antibody responses against factor VIII in healthy individuals and in different cohorts of hemophilia A patients

Nonneutralizing antibodies against factor VIII and risk of inhibitor development in severe hemophilia A

Long‐term anti‐FVIII antibody response in Bethesda‐negative haemophilia A patients receiving continuous replacement therapy

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