Recombinant Factor Viii, Family History, and High-titer Inhibitor Risk in Severe Hemophilia a
Year: 2026
Type: article
Study design: Observational Study
Abstract: Introduction Severe hemophilia A is a hereditary coagulopathy whose chronic treatment with factor VIII (FVIII) concentrates can be complicated by the development of anti-FVIII inhibitors, compromising therapeutic efficacy. Among the factors associated with this outcome, family history of inhibitors and the type of replacement product used, recombinant (rFVIII) or plasma-derived (pFVIII), stand out as a question still debated in the literature. Objective: This study aimed to analyze the association between these variables and inhibitor development in patients with severe hemophilia A followed at the Pernambuco Foundation of Hematology and Hemotherapy (HEMOPE), Recife unit. Methodology: This is an observational, cross-sectional, retrospective study, conducted between June and July 2025, with 47 adult patients, whose clinical, laboratory, and therapeutic data were extracted from medical records and analyzed using chi-square, Fisher's exact test, and the Mann-Whitney test, with odds ratio calculation and p < 0.05. Results and discussion High-titer inhibitors were identified in 37.5% of the sample. A statistically significant association was observed between product type and this outcome, with 36% of patients treated with rFVIII developing inhibitors versus 13% of those treated with pFVIII; and between positive family history and inhibitor development, present in 77.8% of these patients versus 5.6% among those with unknown history, both with odds roughly three to four times higher, although without significance in the isolated comparison. These findings align with post-hoc analyses from the SIPPET study, which identified a higher inhibitor risk within the first ten days of FVIII exposure, this risk being, within the first five days, three to four times higher with recombinant than with plasma-derived products. Mechanistically, plasma-derived FVIII carries von Willebrand factor and immunomodulatory proteins that may reduce its immunogenicity, whereas recombinant products, derived from non-human mammalian cell lines, undergo post-translational modifications that generate neoantigens. Studies show a gene-environment interaction whereby genetically low-risk patients are not protected from this greater immunogenicity when exposed to rFVIII, reaching 43% inhibitor development in this group, versus no cases among those treated with pFVIII. Conclusion It is concluded that both family history and product type are relevant factors in high-titer inhibitor formation, reinforcing the importance of considering them in individualized therapeutic selection, especially in previously untreated patients.
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W7223097582