Can activated recombinant factor VII be used to postpone the exposure of infants to factor VIII until after 2 years of age?

Rivard, G. E.; Lillicrap, David; Poon, Man‐Chiu; Demers, Christine; Lépine, M.; St‐Louis, Jean; Warner, Margaret

doi:10.1111/j.1365-2516.2005.01088.x

Cited by 26 publications

(20 citation statements)

References 18 publications

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“…in a small pilot study in which the aim was to use rFVIIa in place of FVIII until the age of 2 years. Of the 11 infants in this study, six still required FVIII to control bleeding and four subsequently developed inhibitors, which suggests that this is unlikely to be a feasible approach [11].…”

Section: Discussionmentioning

confidence: 99%

Early factor VIII exposure and subsequent inhibitor development in children with severe haemophilia A

Chalmers¹,

Brown²,

Keeling³

et al. 2007

Haemophilia

164

133

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Summary. Recent reports have suggested that the incidence of inhibitors in haemophilia is the highest in those first exposed to factor VIII under 6 months of age. In this study, we investigated inhibitor development in children first exposed to FVIII as neonates and also examined the effect of other genetic and environmental variables. Three hundred and forty-eight children with severe haemophilia A were investigated. Inhibitors developed in 68 of 348 (20%), with 34 of 348 (10%) high titre inhibitors. The incidence in relation to initial FVIII exposure was: <1 month nine of 35 (26%), 1-6 months 13 of 51 (25%), 6-12 months 27 of 130 (21%), 12-18 months 13 of 66 (20%) and >18 months six of 66 (9%). While we observed a significant difference in inhibitor development and age at first exposure across all age groups (P ¼ 0.018), no significant difference was observed in children treated at different time points during the first year of life (P ¼ 0.44). Similar results were obtained for high titre inhibitors. There was also no difference in the incidence of inhibitors in relation to initial FVIII exposure in a subgroup of 144 children with the intron 22 mutation. Inhibitors developed more frequently in those initially treated with recombinant when compared with plasma-derived FVIII (P ¼ 0.006) and in those with a major molecular defect (P ¼ 0.009). In this study, exposure to FVIII during the neonatal period was not associated with a higher incidence of inhibitors than those treated later during the first year of life. Initial treatment with recombinant FVIII and the presence of a major molecular defect were the most important variables affecting inhibitor development.

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Section: Discussionmentioning

confidence: 99%

Early factor VIII exposure and subsequent inhibitor development in children with severe haemophilia A

Chalmers¹,

Brown²,

Keeling³

et al. 2007

Haemophilia

164

133

View full text Add to dashboard Cite

show abstract

“…Rivard and colleagues completed a prospective trial in 11 pediatric patients with severe hemophilia using recombinant factor VIIa to try and postpone exposure to FVIII until after 2 years of age [Rivard et al 2005]. Owing to inadequate hemostasis with recombinant factor VIIa, especially in mouth bleeding, only 3 out of 11 children could postpone FVIII exposure until after 2 years of age [Rivard et al 2005], making this therapeutic option limited. Challenges remain as to the most effective manner in which to minimize a patient's risk of inhibitor formation and further studies are required.…”

Section: Stratification Of Inhibitor Riskmentioning

confidence: 99%

Factor VIII inhibitors in hemophilia A: rationale and latest evidence

Witmer

Young

2012

Therapeutic Advances in Hematology

194

219

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Factor VIII (FVIII) replacement therapy is the foundation of treatment in hemophilia A and is effective unless a patient develops an alloantibody (inhibitor) against exogenous FVIII. Inhibitor development is currently the most significant treatment complication seen in patients with hemophilia and is associated with considerable morbidity and a decreased quality of life. The development of an inhibitor is the result of a complex interaction between a patient's immune system and genetic and environmental risk factors. The mainstay of treatment is the eradication of the inhibitor through immune tolerance. This review summarizes the current evidence regarding inhibitor risk factors, eradication, and hemostatic bypassing agents.

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“…Somewhat paradoxically, it was reported that inhibitor formation was more frequent in patients that initiated IV injections of human FVIII before 6 months of age than for those that started therapy after 6 months [Lorenzo et al, 2001;van der Bom et al, 2003], which would appear to argue against using early administration of protein therapy to prevent inhibitors. However, other studies suggest that the specific hFVIII mutation and/or initiation with episodic therapy in response to bleeds rather than frequent prophylaxis may be critical [Rivard et al, 2005;Chalmers et al, 2007;Santagostino et al, 2005;Kulkarni et al, 2006]. A trial in which protein therapy is initiated with high and frequent administration of human FVIII would be difficult due to problems with IV access in newborn patients.…”

Section: Efficacy Of Neonatal Tolerance To Human Fviii In Humansmentioning

confidence: 94%

Immunology of Neonatal Gene Transfer

Ponder

2007

CGT

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Gene therapy could result in the permanent correction or amelioration of the clinical manifestations of many genetic diseases. However, immune responses to the therapeutic protein pose a significant hurdle for successful gene therapy. Problematic immune responses can include the development of a cytotoxic T lymphocyte (CTL) response that results in the destruction of genetically-modified cells and/or the formation of antibodies directed against the therapeutic protein. One approach to avoid an immune response is to perform gene therapy in newborns, which takes advantage of the fact that the immune system is relatively immature at birth. This approach has been highly effective in mice, and has resulted in stable expression without antibody formation for proteins that are highly immunogenic after transfer to adults. High levels of expression after neonatal gene therapy were more effective at inducing tolerance than low levels of expression in mice, which suggests that high antigen levels are more efficient at inducing tolerance. A criticism of this approach is that the murine immune system is less mature at birth than the immune systems of larger animals. Indeed, neonatal gene therapy to cats with mucopolysaccharidosis I resulted in a CTL response that destroyed expressing cells. Nevertheless, the immune system was still relatively immature, as transient administration of a single immunosuppressive agent at the time of neonatal gene therapy resulted in stable expression. Neonatal administration can reduce, but not eliminate, immune responses after gene therapy.

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Can activated recombinant factor VII be used to postpone the exposure of infants to factor VIII until after 2 years of age?

Cited by 26 publications

References 18 publications

Early factor VIII exposure and subsequent inhibitor development in children with severe haemophilia A

Early factor VIII exposure and subsequent inhibitor development in children with severe haemophilia A

Factor VIII inhibitors in hemophilia A: rationale and latest evidence

Immunology of Neonatal Gene Transfer

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