Research and practice in thrombosis and haemostasis · 2026
Isolated A1-domain F8 large deletions are associated with favorable immune tolerance induction outcomes in children with severe hemophilia A.
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Li Zhengping, Chen Zhenping, Zhang Jialu, Mao Yinqi, Li Zekun, Liu Guoqing, Yao Wanru, Ai Di, Wu Wenman, Wu Runhui
Аннотация
BACKGROUND: Large F8 deletions are generally associated with unfavorable immune tolerance induction (ITI) outcomes in children with severe hemophilia A. Whether intragenic deletion location further stratifies ITI outcomes remains unclear.
OBJECTIVES: To evaluate the association between the location of F8 large deletion and ITI outcome in children with severe hemophilia A and to exploratorily assess residual F8 expression across patients with different deletion locations.
METHODS: This single-center, retrospective cohort included 34 children with severe hemophilia A, F8 large deletions, inhibitors, and evaluable ITI outcomes. Deletions were mapped to factor VIII (FVIII) domains and categorized as isolated A1-domain or nonisolated A1-domain deletions. Exploratory F8 mRNA and protein analyses were performed in patients with available blood samples.
RESULTS: Thirteen patients achieved ITI success or partial success, and 21 experienced ITI failure. Success or partial success was more frequent with isolated A1-domain than nonisolated A1-domain deletions (8/9 vs 5/25; P < .001). Higher historical peak, pre-ITI, and on-ITI peak inhibitor titers were associated with failure in univariate analyses. After multivariable adjustment, isolated A1-domain deletion remained associated with higher odds of success or partial success (adjusted odds ratio, 21.59; 95% confidence interval, 1.24-375.60; P = .035). Residual downstream F8 transcripts were detected in the isolated A1-domain subgroup; their biological relevance remains uncertain.
CONCLUSIONS: Intragenic location of F8 large deletions was associated with ITI outcome in this cohort. Isolated A1-domain deletions may identify patients with a more favorable ITI prognosis. Exploratory expression findings require confirmation in larger studies using physiologically relevant models.
OBJECTIVES: To evaluate the association between the location of F8 large deletion and ITI outcome in children with severe hemophilia A and to exploratorily assess residual F8 expression across patients with different deletion locations.
METHODS: This single-center, retrospective cohort included 34 children with severe hemophilia A, F8 large deletions, inhibitors, and evaluable ITI outcomes. Deletions were mapped to factor VIII (FVIII) domains and categorized as isolated A1-domain or nonisolated A1-domain deletions. Exploratory F8 mRNA and protein analyses were performed in patients with available blood samples.
RESULTS: Thirteen patients achieved ITI success or partial success, and 21 experienced ITI failure. Success or partial success was more frequent with isolated A1-domain than nonisolated A1-domain deletions (8/9 vs 5/25; P < .001). Higher historical peak, pre-ITI, and on-ITI peak inhibitor titers were associated with failure in univariate analyses. After multivariable adjustment, isolated A1-domain deletion remained associated with higher odds of success or partial success (adjusted odds ratio, 21.59; 95% confidence interval, 1.24-375.60; P = .035). Residual downstream F8 transcripts were detected in the isolated A1-domain subgroup; their biological relevance remains uncertain.
CONCLUSIONS: Intragenic location of F8 large deletions was associated with ITI outcome in this cohort. Isolated A1-domain deletions may identify patients with a more favorable ITI prognosis. Exploratory expression findings require confirmation in larger studies using physiologically relevant models.