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Risk of Inhibitor Development in Children with Haemophilia A
increased the risk of inhibitor development in severe haemophilia mutation type, reason for first treatment and FVIII concentrate product
patients. In a multicentre cohort study, a shorter duration between type. Similarly, a study investigating inhibitor development in children
exposure days increased the risk of inhibitor development.
9
In addition, first exposed to FVIII as neonates found that the effect of age at first
there appeared to be an association between the dose of FVIII and exposure disappeared after adjustment for intensive treatment.
7
inhibitor development. However, this link lessened after adjustments
for other confounding factors were made. Biological evidence Type of Factor Used
indicates that a higher dose of FVIII will lead to an increased risk The potential difference between products was first noted with the
of inhibitor development.
29
Major injuries and surgeries cause tissue introduction of virus-inactivated concentrates.
33,34
With the introduction
damage and inflammation. Damaged cells from injured areas send of recombinant FVIII (rFVIII), the focus has shifted to differences between
‘danger signals’, which activate FVIII antigen-presenting cells, these products and plasma-derived FVIII (pdFVIII). However, studies with
upregulating co-stimulatory signals to T lymphocytes. Both FVIII- both pdFVIII and rFVIII in previously untreated patients have produced a
expressing antigen-presenting cells and T lymphocytes enhance the large range of inhibitor development rates. Moreover, retrospective
formation of antibodies to FVIII in B lymphocytes. studies comparing pdFVIII and rFVIII have produced conflicting results.
Goudemand et al. reported that rFVIII was associated with a higher risk
Prophylaxis Treatment of inhibitor development compared with high-purity pdFVIII, regardless of
There is increasing evidence that prophylaxis regimens reduce the risk of other risk factors.
6
This is in contrast to findings from the recent CANAL
inhibitor development compared with bolus on-demand treatment in terms study, which showed that there was no significant difference in the risk
of exposure to FVIII.
30
A recent study reported that 78% of previously of inhibitor development between patients who received the pdFVIII and
untreated children with severe haemophilia A treated with on-demand FVIII patients treated with rFVIII.
35
These results highlight the difficulty in
replacement developed inhibitors compared with 0% in the prophylaxis directly comparing data from retrospective studies due to confounding
group.
16
Owing to the similarities in terms of of genetic mutations and age factors such as differences in study design, the inherent heterogenicity of
in the prophylaxis and on-demand groups, the authors concluded that concentrate design, inhibitor diagnostics and diagnostic intervals.
on-demand therapy represents a clear risk factor for the development of
inhibitors. Further support for the use of prophylaxis in children with severe
haemophilia A came from a study evaluating environmental risks for the
There is increasing evidence that
development of inhibitors in children with moderate to severe haemophilia
A.
31
A univariate analysis was used to demonstrate that commencing
prophylaxis regimens reduce the risk of
prophylaxis before the age of 35 months carried an inhibitor risk of 28%
inhibitor development compared with
compared with a 56% risk in patients treated with on-demand therapy.
bolus on-demand treatment in terms of
The protective effect seen from use of prophylaxis remained significant
after adjustments for genetic and environmental factors. The results of this exposure to factor VIII.
study support the use of prophylaxis in children, even in those with a high
risk of inhibitor development.
More recently, it was reported that inhibitor development was lower in
The ‘danger theory’ of tolerance proposes that the immune system haemophilia A patients treated with a high-purity pdFVIII product
responds to danger signals from both exogenous and endogenous containing von Willebrand factor (vWF) compared with those treated with
sources.
32
If an antigen is not itself perceived as dangerous and no other rFVIII.
36
However, it is unclear whether the brand of product or the high-
danger signals – such as cell necrosis or tissue injury – are present, purity nature of the pdFVIII used accounts for the lower incidence of
tolerance normally occurs rather than an immune response. Thus, inhibitor development. In the CANAL study, patients treated with pdFVIII
theoretically, a prophylactic regimen may offer a protective effect since products containing small concentrations of vWF had a lower incidence of
the patient is treated in the absence of any additional danger signals, inhibitors, although the patient number was too small to confirm this
whereas on-demand administration of FVIII may be perceived as finding.
35
It has been suggested that vWF may protect FVIII from
dangerous due to danger signals from ongoing bleeding episodes or circulating antibodies by altering antibody epitopes on the C2 domain.
37–39
during physiological stress such as surgery. It has been reported that mice treated with FVIII alone developed higher
peak inhibitors compared with those treated with FVIII containing vWF.
40
Other Treatment-related Factors However, it should be noted that the validity of the FVIII exon 17 knockout
mouse model utilised in the study has been questioned. It has been argued
Age at First Exposure that the vWF/FVIII combination may have induced a dual immunogenic
Age at first exposure as an independent risk factor has been a subject of challenge in the murine model, resulting in antigenic competition that
much debate. While early studies have reported a link between the could have suppressed the immune response to FVIII.
41
development of inhibitors and the age at which children start FVIII
treatment,
15,19
when genetic factors are taken into account the Although it was previously suspected that there might be an impact on
differences are not statistically significant.
31
In the CANAL cohort study, inhibitor development, evidence from large-scale studies shows that
the risk of inhibitor development in patients treated with FVIII before the there was no conspicuous increase in inhibitor development when
first month of age was 41% compared with 18% in those who started patients were switched between different products during treatment.
FVIII treatment after the age of 18 months.
18
However, once again the The recent CANAL study examined whether changing between FVIII
link between inhibitor development and age at first exposure became products altered inhibitor risk in 316 previously untreated patients with
insignificant after accounting for other factors such as ethnicity, gene severe haemophilia A.
35
No difference was noted in patients who had
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