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- de Kovel, Marloes S., et al.
(author)
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Bleeding phenotype according to factor level in 825 children with nonsevere hemophilia : data from the PedNet cohort
- 2024
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In: Journal of Thrombosis and Haemostasis. - 1538-7933.
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Journal article (peer-reviewed)abstract
- Background: Information on bleeding phenotype in nonsevere hemophilia may be used to determine target factor levels for prophylaxis or gene therapy in severe hemophilia. Objectives: To assess the association between endogenous factor level and bleeding phenotype in children with nonsevere (factor [F]VIII/FIX activity 1%-25%) hemophilia A (HA) and B without prophylaxis. Methods: Data on annualized bleeding rate (ABR), annualized joint bleeding rate (AJBR), and onset of bleeding were extracted from the international PedNet cohort including children born since 2000. Mean ABR and AJBR were modeled and compared according to FVIII/FIX endogenous activity (1%-2%, 3%-5%, 6%-10%, 11%-15%, 16%-20%, and 21%-25%) using negative binomial regression. Onset of bleeding was analyzed using Kaplan–Meier survival curves. Results: Eight hundred twenty-five children (40% with moderate hemophilia; 87% with HA) with median follow-up of 7.4 years/child were included. The median age at onset of bleeding and median bleeding rates changed with increasing endogenous activity. From endogenous FVIII 1% to 2% to 21% to 25%, the age at onset of bleeding changed from a median of 1.4 to 14.2 years, ABR from 1.6 to 0.1/y, and AJBR from 0.5 to 0.0/y. From endogenous FIX 1% to 2% to 16% to 25%, the onset of bleeding changed from a median of 1.7 to 6.1 years, ABR from 0.5 to 0.1/y, and AJBR from 0.1 to 0.0/y. The negative correlation between AJBR and factor level was most strongly pronounced up to a factor level of 6% in HA and hemophilia B. Conclusion: Endogenous factor activity of >5% was identified as a threshold to significantly lower joint bleeding rate, while FVIII levels >15% and FIX levels >10% were sufficient to achieve the goal of 0 bleeds in this pediatric cohort.
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- Gouw, Samantha C., et al.
(author)
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Factor VIII Products and Inhibitor Development in Severe Hemophilia A
- 2013
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In: New England Journal of Medicine. - 0028-4793. ; 368:3, s. 231-239
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Journal article (peer-reviewed)abstract
- Background For previously untreated children with severe hemophilia A, it is unclear whether the type of factor VIII product administered and switching among products are associated with the development of clinically relevant inhibitory antibodies (inhibitor development). Methods We evaluated 574 consecutive patients with severe hemophilia A (factor VIII activity, <0.01 IU per milliliter) who were born between 2000 and 2010 and collected data on all clotting-factor administration for up to 75 exposure days. The primary outcome was inhibitor development, which was defined as at least two positive inhibitor tests with decreased in vivo recovery of factor VIII levels. Results Inhibitory antibodies developed in 177 of the 574 children (cumulative incidence, 32.4%); 116 patients had a high-titer inhibitory antibody, defined as a peak titer of at least 5 Bethesda units per milliliter (cumulative incidence, 22.4%). Plasma-derived products conferred a risk of inhibitor development that was similar to the risk with recombinant products (adjusted hazard ratio as compared with recombinant products, 0.96; 95% confidence interval [CI], 0.62 to 1.49). As compared with third-generation full-length recombinant products (derived from the full-length complementary DNA sequence of human factor VIII), second-generation full-length products were associated with an increased risk of inhibitor development (adjusted hazard ratio, 1.60; 95% CI, 1.08 to 2.37). The content of von Willebrand factor in the products and switching among products were not associated with the risk of inhibitor development. Conclusions Recombinant and plasma-derived factor VIII products conferred similar risks of inhibitor development, and the content of von Willebrand factor in the products and switching among products were not associated with the risk of inhibitor development. Second-generation full-length recombinant products were associated with an increased risk, as compared with third-generation products. (Funded by Bayer Healthcare and Baxter BioScience.)
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- Gouw, Samantha C., et al.
(author)
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Recombinant versus plasma-derived factor VIII products and the development of inhibitors in previously untreated patients with severe hemophilia A: the CANAL cohort study
- 2007
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In: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 109:11, s. 4693-4697
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Journal article (peer-reviewed)abstract
- It has been suggested that plasma-derived factor VIII products induce fewer inhibitors than recombinant factor VIII products. We investigated the relationship of factor VIII product type and switching between factor VIII products with the risk to develop inhibitors. This multicenter retrospective cohort study included 316 patients with severe hemophilia A born between 1990 and 2000. The outcome was clinically relevant inhibitor development, defined as the occurrence of at least 2 positive inhibitor titers with decreased recovery. The risk of inhibitor development was not clearly lower in plasma-derived compared with recombinant factor VIII products (relative risk [RR],. 0.8; 95% confidence interval [CI], 0.5-1.3). Among high-titer inhibitors, the possible reduction in risk was even less pronounced (RR, 0.9; CI, 0.5-1.5). Plasma-derived products with considerable quantities of von Willebrand factor (VWF) carried the same risk for inhibitor development as recombinant factor VIII products (RR, 1.0; CI, 0.6-1.6). Switching between factor VIII products did not increase the risk for inhibitors (RR, 1.1; CI, 0.6-1.8). In conclusion, our findings support neither the notion that plasma-derived factor VIII products with considerable concentrations of VWF confer a lower risk to develop inhibitory antibodies than recombinant factor VIII products, nor that switching between factor VIII product brands increases inhibitor risks in previously untreated patients with severe hemophilia A.
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- Ranta, Susanna, et al.
(author)
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Dilemmas on emicizumab in children with haemophilia A : A survey of strategies from PedNet centres
- 2023
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In: Haemophilia. - 1351-8216. ; 29:5, s. 1291-1298
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Journal article (peer-reviewed)abstract
- Introduction: Haemophilia A care has changed with the introduction of emicizumab. Experience on the youngest children is still scarce and clinical practice varies between haemophilia treatment centres. Aim: We aimed to assess the current clinical practice on emicizumab prophylaxis within PedNet, a collaborative research platform for paediatricians treating children with haemophilia. Methods: An electronic survey was sent to all PedNet members (n = 32) between October 2022 and February 2023. The survey included questions on the availability of emicizumab, on the practice of initiating prophylaxis in previously untreated or minimally treated patients (PUPs or MTPs) and emicizumab use in patients with or without inhibitors. Results: All but four centres (28/32; 88%) responded. Emicizumab was available in clinical practice in 25/28 centres (89%), and in 3/28 for selected patients only (e.g. with inhibitors). Emicizumab was the preferred choice for prophylaxis in PUPs or MTPs in 20/25 centres; most (85%) started emicizumab prophylaxis before 1 year of age (30% before 6 months of age) and without concomitant FVIII (16/20; 80%). After the loading dose, 13/28 centres administered the recommended dosing, while the others adjusted the interval of injections to give whole vials. In inhibitor patients, the use of emicizumab during ITI was common, with low-dose ITI being the preferred protocol. Conclusion: Most centres choose to initiate prophylaxis with emicizumab before 12 months of age and without concomitant FVIII. In inhibitor patients, ITI is mostly given in addition to emicizumab, but there was no common practice on how to proceed after successful ITI.
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