Diagnosis and management of haemophilia

Fijnvandraat, Karin; Cnossen, Marjon H.; Leebeek, Frank W.G.; Peters, Marjolein

doi:10.1136/bmj.e2707

Cited by 93 publications

(119 citation statements)

References 31 publications

(22 reference statements)

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“…1,2 Inhibitor development is one of the most challenging complications in the treatment of hemophilia A, as it increases the bleeding tendency while it renders treatment with therapeutic factor VIII concentrates ineffective. The online version of the article contains a data supplement.…”

Section: Introductionmentioning

confidence: 99%

Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A

Eckhardt

Velzen

Peters

et al. 2013

Blood

190

263

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Key Points• The inhibitor incidence in nonsevere hemophilia A patients with certain F8 mutations approaches the inhibitor incidence in severe patients.• These findings are highly relevant for clinical practice, as they facilitate identification of high-risk patients based on F8 genotype.Neutralizing antibodies (inhibitors) toward factor VIII form a severe complication in nonsevere hemophilia A, profoundly aggravating the bleeding pattern. Identification of high-risk patients is hampered by lack of data that take exposure days to therapeutic factor VIII concentrates into account. In the INSIGHT study, we analyzed the association between F8 mutation and inhibitor development in patients with nonsevere hemophilia A (factor VIII 2-40 IU/dL). This analysis included 1112 nonsevere hemophilia A patients from 14 centers in Europe and Australia that had genotyped at least 70% of their patients. Inhibitor risk was calculated as KaplanMeier incidence with cumulative number of exposure days as the time variable. During 44 800 exposure days (median, 24 exposure days per patient; interquartile range [IQR], 7-90), 59 of the 1112 patients developed an inhibitor; cumulative incidence of 5.3% (95% confidence interval [CI], 4.0-6.6) after a median of 28 exposure days (IQR,. The inhibitor risk at 50 exposure days was 6.7% (95% CI, 4.5-8.9) and at 100 exposure days the risk further increased to 13.3% (95% CI, 9.6-17.0). Among a total of 214 different F8 missense mutations 19 were associated with inhibitor development. These results emphasize the importance of F8 genotyping in nonsevere hemophilia A. (Blood. 2013; 122(11):1954-1962 IntroductionPatients with hemophilia A who are treated with factor VIII concentrates are at risk of developing factor VIII neutralizing alloantibodies (inhibitors).1,2 Inhibitor development is one of the most challenging complications in the treatment of hemophilia A, as it increases the bleeding tendency while it renders treatment with therapeutic factor VIII concentrates ineffective. Although inhibitor development is less frequently observed in patients with nonsevere hemophilia A (baseline factor VIII activity of 2-40 IU/dL), the clinical impact can be profound. In these patients, inhibitors may also interact with their endogenous factor VIII, resulting in a decrease of the factor VIII plasma level below 1 IU/dL 1 and major bleeding complications. 4 Identification of patients at risk of developing inhibitors may help to prevent this serious complication. However, currently there are no tools available to predict individual inhibitor risk in nonsevere hemophilia patients.The type of mutation in the factor VIII gene (F8) is an important risk factor for inhibitor development. [5][6][7] Nonsevere hemophilia A is generally caused by F8 missense mutations.8 Despite information on large numbers of F8 mutations associated with nonsevere hemophilia A that is collected in international databases, 9,10 it is not possible to calculate the inhibitor risk for specific F8 mutations, as data on exposure days to thera...

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Section: Introductionmentioning

confidence: 99%

Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A

Eckhardt

Velzen

Peters

et al. 2013

Blood

190

263

View full text Add to dashboard Cite

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“…Patients with this condition Thrombosis Research xxx (2015) xxx-xxx have bleeding episodes in joints and tissues and, if untreated, experience long-term morbidity [1].…”

Section: Introductionmentioning

confidence: 99%

Physicochemical characterisation of rVIII-SingleChain, a novel recombinant single-chain factor VIII

Schmidbauer

Witzel

Robbel

et al. 2015

Thrombosis Research

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“…[1][2][3] In a recent cohort study, 23% of patients with mild hemophilia were positive for hepatitis C virus, a proportion substantially lower than in patients with severe hemophilia. 3,4 In patients with mild hemophilia A (MHA), excessive bleeding usually occurs after minor trauma, dental procedures, or surgery. This is unlike patients with severe deficiency (FVIII , 1 U/dL), who frequently bleed spontaneously without preceding trauma.…”

Section: Introductionmentioning

confidence: 99%

“…3,4 Inhibitor development risk in MHA: not so early, not so low Some patients with MHA may develop inhibitory antibodies after treatment with FVIII concentrates, with a prevalence of 5% to 10%. 5,7,8 When exposure days (ED) are taken into account, the risk for inhibitor development clearly increases with the number of ED to exogenous, therapeutic FVIII concentrates.…”

Section: Introductionmentioning

confidence: 99%

“…8 This indicates that inhibitor development may occur throughout the lifetime in MHA, in contrasting to patients with severe hemophilia A, who have the highest risk for inhibitor development at 10 to 15 days, which becomes almost negligible at 50 ED or more. 4 Molecular and clinical predictors of inhibitor risk in MHA FVIII missense mutations are the main cause of MHA, although about 5% to 10% of patients may have splicing defects, point deletions, deep intronic changes, or promoter mutations. 9 Of interest, it has been definitely demonstrated that among more than 150 different causative missense mutations for MHA, some relatively frequent mutations are associated with a high risk for inhibitor development on replacement therapy.…”

Section: Introductionmentioning

confidence: 99%

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Molecular and clinical predictors of inhibitor risk and its prevention and treatment in mild hemophilia A

Castaman

Fijnvandraat²

2014

Blood

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The risk for inhibitor development in mild hemophilia A (factor VIII levels between 5 and 40 U/dL) is larger than previously anticipated, continues throughout life, and is particularly associated with certain mutations in F8. Desmopressin may reduce inhibitor risk by avoiding exposure to FVIII concentrates, but the heterogenous biological response to desmopressin, showing large interindividual variation, may limit its clinical use. However, predictors of desmopressin response have been recently identified, allowing the selection of the best candidates to this treatment.

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Diagnosis and management of haemophilia

Cited by 93 publications

References 31 publications

Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A

Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A

Physicochemical characterisation of rVIII-SingleChain, a novel recombinant single-chain factor VIII

Molecular and clinical predictors of inhibitor risk and its prevention and treatment in mild hemophilia A

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