Factor VIII Products and Inhibitor Development in Severe Hemophilia A
Open accessAbstract
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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No HA gene-therapy subjects have developed an inhibitor.
“Consistent with 2 decades of experience with rFVIII-SQ ERT, demonstrating no increased inhibitor risk, no HA gene-therapy subjects have developed an inhibitor.196, 197, 198”
From Current clinical applications of in vivo gene therapy with AAVs (2021) · cites this paper as [196]
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D'Agostino, R. B., Lee, M., Belanger, A. J., Cupples, L. A., Anderson, K., & Kannel, W. B. (1990) · Statistics in Medicine · doi:10.1002/sim.4780091214 · Cited by 798 · see citing works
Incidence of factor VIII inhibitors throughout life in severe hemophilia A in the United Kingdom
Hay, C. R. M., Palmer, B., Chalmers, E., Liesner, R., Maclean, R., Rangarajan, S., Williams, M., Collins, P. W., & on behalf of United Kingdom Haemophilia Centre Doctors' Organisation (UKHCDO) (2011) · Blood · doi:10.1182/blood-2010-09-308668 · Cited by 174 · see citing works
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Current clinical applications of in vivo gene therapy with AAVs
Mendell, J. R., Al-Zaidy, S. A., Rodino-Klapac, L. R., Goodspeed, K., Gray, S. J., Kay, C. N., Boye, S. L., Boye, S. E., George, L. A., Salabarria, S., et al. (2021) · Molecular Therapy · doi:10.1016/j.ymthe.2020.12.007 · Cited by 743 · see citing works
The past and future of haemophilia: diagnosis, treatments, and its complications
Peyvandi, F., Garagiola, I., & Young, G. (2016) · The Lancet · doi:10.1016/s0140-6736(15)01123-x · Cited by 505 · see citing works
Crudele, J. M., Finn, J. D., Siner, J. I., Martin, N. B., Niemeyer, G. P., Zhou, S., Mingozzi, F., Lothrop, C. D., & Arruda, V. R. (2015) · Blood · doi:10.1182/blood-2014-07-588194 · Cited by 153 · see citing works
Protein-Engineered Coagulation Factors for Hemophilia Gene Therapy
Samelson-Jones, B. J., & Arruda, V. R. (2019) · Molecular Therapy - Methods & Clinical Development · doi:10.1016/j.omtm.2018.12.007 · Cited by 58 · see citing works
- Authors
- Gouw, S. C., van der Bom, J. G., Ljung, R., Escuriola, C., Cid, A. R., Claeyssens-Donadel, S., van Geet, C., Kenet, G., Mäkipernaa, A., Molinari, A. C., Muntean, W., Kobelt, R., Rivard, G., Santagostino, E., Thomas, A., & van den Berg, H. M.
- Affiliations
- University Medical Center Utrecht (NL)
- Lund University (SE)
- University Hospital Frankfurt (DE)
- Hospital Universitari i Politècnic La Fe (ES)
- Sheba Medical Center (IL)
- University of Helsinki (FI)
- Istituto Giannina Gaslini (IT)
- University of Bern (CH)
- Centre Hospitalier Universitaire Sainte-Justine (CA)
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT)
- Royal Hospital for Sick Children (GB)
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2013-01-17
- Volume
- 368
- Issue
- 3
- Pages
- 231-239
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W1963967196
- Cited by
- 440
- References
- 2
- Citations by year
- 2026: 10 · 2025: 12 · 2024: 21 · 2023: 21 · 2022: 28 · 2021: 22 · 2020: 29 · 2019: 20 · 2018: 47 · 2017: 40 · 2016: 53 · 2015: 43 · 2014: 61 · 2013: 31
- FWCI
- 44.97
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- INFM-OAR (INFN Catania) (submittedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Hematology › Hemophilia Treatment and Research
- Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
- Health Sciences › Medicine › Genetics › Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Keywords
- hemophilia A, factor VIII inhibitors, inhibitor development, recombinant factor VIII, plasma-derived factor VIII, von Willebrand factor, product switching, children
- MeSH terms
- Antibodies, Child, Factor VIII, Hemophilia A, Humans, Male, von Willebrand Factor
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