The Prevalence of Non-Neutralizing Anti-FVIII Antibodies in the Canadian Hemophilia Population.
Bibliographic record
Abstract
Abstract Abstract 1291 Poster Board I-313 Introduction In approximately 25% of hemophilia A patients, inhibitory anti-FVIII antibodies develop following treatment with FVIII protein infusion therapy. This is currently the most serious treatment-related complication in this population. While the presence of these antibodies has been evaluated by a functional clotting assay for the past 30 years (the Bethesda Assay), there is a growing appreciation that the anti-FVIII immune response may also include the appearance of non-neutralizing antibodies in some patients. The prevalence, natural history and clinical relevance of these antibodies are the subject of this study. Methods Plasma samples from 602 hemophilia A patients formed the study material for this project. These samples had been stored at –80C since the conversion from plasma-derived to recombinant FVIII (rFVIII) concentrates in Canada. The results of prior Bethesda assay testing were available for 392 of these samples. The ELISA-based test for non-neutralizing anti-FVIII antibodies utilized three different rFVIII products as antigens: two full-length rFVIII products and one B domain-deleted rFVIII. Each microtiter plate run included six negative and one positive control sample. All samples were tested in duplicate and samples with positive results (absorbance >mean + 3SD) were subjected to serial dilution testing. 93 of the samples were also tested by the same assay in a second laboratory. Results Anti-FVIII antibodies were documented using this ELISA-based assay in 11.5% of this population. 11.5% and 8.8% of the patients demonstrated non-neutralizing antibodies to the two full-length rFVIII concentrates Advate® and Kogenate®, respectively. In contrast, antibodies to the B domain-deleted concentrate, Xyntha®, were only found in 4.6% of patients. 2.8% of patients had antibodies to all three concentrates while 3.1% of patients had antibodies to only Advate (2.8%) or Kogenate (0.3%). Twenty four of the 392 patients (6.1%) tested with the Bethesda assay had inhibitory anti-FVIII antibodies (range 0.6 – 267 BUs). A third of these Bethesda +ve cases demonstrated positivity in this assay to all three rFVIII products, while another 30% had antibodies against one or two of the rFVIII concentrates. 48 of the 368 cases that tested negative in the Bethesda assay were positive for non-neutralizing anti-FVIII antibodies (13%). To date, 20 of the samples testing positive for non-neutralizing antibodies have been studied by serial dilution analysis and 9 of these samples were only positive at the initial dilution of 1:50. Seven cases had positive dilution titers of 1:200 (3 with inhibitory antibodies ranging from 0.6 to 98 BUs) and two samples were positive at a dilution of 1:400, both of which had positive Bethesda results of 30 and 115 BUs, respectively. To assess the inter-laboratory consistency of this testing protocol, 93 selected samples were assayed with the identical methodology in a second laboratory. These studies showed positive results for the presence of antibodies to the two full-length rFVIIIs in 32-45% of cases. In contrast, the range of positive results for the two laboratories with the B domain-deleted rFVIII was between 19 and 37%. Conclusions This study of a large Canadian hemophilia A population has demonstrated the presence of non-neutralizing anti-FVIII antibodies in 11% of the population. Antibodies to the B domain-deleted rFVIII were significantly less frequent. When evaluated, inhibitory antibodies were present in 6% of this population and in the Bethesda negative cases, non-neutralizing antibodies were found in 13% of patients. Finally, many of these non-neutralizing antibodies appear to be of low titer, and their clinical significance must await further study with clotting factor recovery and half-life analysis. Disclosures No relevant conflicts of interest to declare.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.002 | 0.003 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.004 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".