Paediatric Working Party of UKHCDO: Early factor VIII exposure and subsequent inhibitor development in children with severe haemophilia A

Royal Hospital for Sick Children, Glasgow, UK.
Haemophilia (Impact Factor: 2.6). 04/2007; 13(2):149-55. DOI: 10.1111/j.1365-2516.2006.01418.x
Source: PubMed


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 = 0.018), no significant difference was observed in children treated at different time points during the first year of life (P = 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 = 0.006) and in those with a major molecular defect (P = 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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    • "Potential disadvantages of this treatment include the risk of trauma during the administration of factor concentrates and the likelihood that time in hospital post - delivery will be prolonged . Perhaps more importantly , it has been suggested that early exposure to FVIII in severe haemophilia A is associated with an increased risk of inhibitor development : these data however , have not been confirmed in subsequent studies ( Lorenzo et al , 2001 ; Van der Bom et al , 2003 ; Chalmers et al 2007 ; Gouw et al , 2007 ) . Other areas of uncertainty include the timing and number of doses required to confer potential benefit . "
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    ABSTRACT: In keeping with these data, the increased risk of intra-cranial and extra-cranial bleeding secondary to birth trauma appears to be mirrored in neonates with haemophilia (Ljung et al, 1994; Klinge et al, 1999; Stieltjes et al, 2005; Tarantino et al, 2007; Richards et al, 2009). In one of the first studies to address this issue, Ljung et al (1994) reported data on 117 severe and moderate haemophiliacs born in Sweden between 1970 and 1990. There were 17/117 (14·5%) cases of cranial bleeding, 4/117 (3·5%) ICH, 12/117 (10·3%) extra-cranial haemorrhage (ECH) and 1/117 (0·8%) retro-orbital bleeding (Ljung et al, 1994). Of the 12 subgaleal/cephalic haematomas, 10 had been delivered by ventouse extraction and among the four cases of ICH, one followed ventouse extraction, one followed premature delivery by caesarean section and the other two followed apparently normal vaginal delivery. There was therefore a clear relationship between ventouse at delivery and ECH, but a less clear association with ICH. Several subsequent studies did however show a more definite relationship between ICH and instrumentation at delivery (Klinge et al, 1999; Stieltjes et al, 2005; Tarantino et al, 2007; Richards et al, 2009). In a German registry study (Klinge et al, 1999) 9/11 cases of ICH were associated with trauma at delivery although the details were not specified and Stieltjes et al (2005) reported instrumentation at delivery in 7/10 cases of ICH. In a large population-based study the overall incidence of ICH in the presence of haemophilia or von Willebrand disease was 3·4%, which dropped to 1·9% following exclusion of ventouse deliveries and other co-morbidities (Tarantino et al, 2007).
    British Journal of Haematology 05/2011; 154(2):208-15. DOI:10.1111/j.1365-2141.2010.08545.x · 4.71 Impact Factor
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    • "ment : 2 . 6 ( 1 . 3 – 5 . 1 ) Age at first treatment was not associated with a higher risk of inhibitors after adjustment for confounding factors Regular prophylaxis was associ ated with a 60% lower risk than on demand treatment . Surgical procedures and peak treatment moments at start of treatment were associated with a higher risk of inhibitors Chalmers et al . , 2007 [ 20 ] Retrospective CH 348 <1% PUPs BA ( ‡1 . 0 twice ) ‡1· per 3 – 6 months <1 month : 26% 1 – 6 months : 25% 6 – 12 months : 21% 12 – 18 months : 20% >18 months : 9% Onset of treatment at age <1 month = 1 . 15 ( CI 0 . 47 – 2 . 85 ) P = 0 . 018 across all age groups P = 0 . 44 at different time points during the 1st year of life Expo"
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    ABSTRACT: SUMMARY: The development of inhibitors to the infused factor in patients with haemophilia is a serious clinical problem. Recent evidence suggests that alongside the strong genetic contribution to inhibitor formation, there are a number of non-genetic factors--perceived by the immune system as danger signals--which promote formation of inhibitors. This study provides a comprehensive review of clinical studies relating to these factors and also presents a survey of opinion concerning their importance and clinical influence, conducted among the members of the European Haemophilia Treatment Standardisation Board (EHTSB). Taken together, this information highlights the lack of robust data concerning the influence of several non-genetic risk factors on inhibitor development, and an urgent need for prospective, well-conducted studies that adhere to recommendations made by the European Medicines Agency (EMEA) for studying inhibitors. Based on current literature, the EHTSB formulated consensus recommendations. It is desirable to minimize intensive treatment wherever possible, given the clinical situation. Prophylaxis should be offered to all children, although we still need to determine optimal dosing with respect to inhibitor development, and age for starting treatment. Vaccinations should be given subcutaneously and concomitant factor concentrate infusions avoided. According to the board, there is no evidence in the literature supporting suggestions that the type of concentrate influences inhibitor risk; but all patients should be monitored during their first exposures. Furthermore, there is no evidence to support an association between pregnancy-related issues, breast feeding and treatment-related factors (e.g. route of administration, or use of blood components) and inhibitor development.
    Haemophilia 09/2010; 16(5):747-66. DOI:10.1111/j.1365-2516.2010.02231.x · 2.60 Impact Factor
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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. "
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    ABSTRACT: 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.
    Current Gene Therapy 11/2007; 7(5):403-10. DOI:10.2174/156652307782151434 · 2.54 Impact Factor
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