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Inhibitors in Haemophilia A – Ongoing Research and Clinical Practice
Continuous Infusion in a central laboratory for confirmation and accepted that about one-
In the 1990s, continuous infusion of FVIII concentrates, mainly during third of the patients switched to another product (mainly from pdFVIII
and after surgical interventions, became widespread because this to rFVIII) after a median of five exposure days.
46
Together, these
mode of administration avoids the risks of peak and trough levels protocol details may very well explain why this study failed to
obtained with bolus injections and reduces the amount of concentrate demonstrate a difference. The fourth study comparing the risk of
needed. However, some reports of de novo inhibitors in patients with inhibitor development between the two product types and requiring
a long history of FVIII exposure or in patients with mild haemophilia frequent inhibitor testing is the prospective multicentre GTH PUP
have raised the question of whether this mode of administration Study, initiated 15 years ago by the German, Austrian and Swiss
represents an additional risk factor for inhibitor development, at least Society of Thrombosis and Haemostasis Research. More than 330 PUPs
during surgery, which itself is a stress situation for the immune have been enrolled into this study, but the final analysis of the results
system.
28
To date, the situation is not clear and more data are needed. is not yet available.
Type of Factor VIII Product In conclusion, the trend towards a lower inhibitor risk with pdFVIII
In the last 15 years several studies have investigated the influence of products could be confirmed by at least two of the three completed
the type or brand of FVIII concentrate on inhibitor development in comparative studies. The potential reasons for such a difference are
PUPs.
2,30
Due to great differences in design and patient population, the unclear. One explanation could be differences in the applied
studies resulted in a large range of inhibitor incidences. Nevertheless, purification and virus inactivation methods. Also, the content and
a systematic analysis of the published data could demonstrate a amount of bound VWF seems to play an important role,
30,47
as bound
general trend.
31
Patients treated with a single pdFVIII product had a VWF protects FVIII from endocytosis by antigen-presenting cells.
48
A
lower cumulative inhibitor incidence (0–12.4%) than those treated protective effect of VWF could also be demonstrated in a haemophilia
with a single rFVIII concentrate (36.0–38.7%). Even if the differences A mouse model, where the immunogenicity of VWF-containing
in study design and study population do not allow a direct comparison products was much lower than that of VWF-free concentrates.
49
of these numbers, the lower incidence in patients treated with pdFVIII Another important difference between the two product types could be
remains when only high responders are considered and can be shown the ratio between FVIII antigen and activity, as well as the content of
to be independent of the severity of the disease, the study size or the FVIII that cannot bind to VWF.
50
In plasma-derived products, the
frequency of inhibitor testing.
30
In contrast to the generally higher FVIII:Ag/FVIII:C ratio is almost 1, whereas recombinant products
inhibitor rates in PUPs treated with rFVIII in the 1990s, a more recent contained approximately 25% more antigen than activity; also, the
prospective study with a sucrose-formulated rFVIII product in PUPs and content of FVIII unable to bind to VWFwas quite low in plasma-derived
minimally treated patients revealed a relatively low inhibitor incidence products, but in the range of 20% of the antigen in recombinant
of only 15%,
32
although the genetic and environmental background of products. Non-complexed FVIII presents epitopes to immune-
the patients showed a typical risk profile for severe haemophilia A.
33
competent cells, which are covered in VWF-bound FVIII. Accordingly, a
Figure 1, a summary of the analysed studies,
32,34–44
shows the possible correlation between the antigen surplus and the higher
cumulative inhibitor incidences in PUPs treated with a single pdFVIII or immunogenicity of rFVIII products can be considered.
30
One possible
a single rFVIII product. explanation for the lower inhibitor incidence with the sucrose-
formulated rFVIII product
32
might be that the VWF-binding capacity is
There are four studies comparing the effect of pdFVIII and rFVIII on increased and the content of free FVIII is minimised by the improved
inhibitor incidence in PUPs with haemophilia A. Three are retrospective – purification process used for this product. In addition to the various
the French cohort study,
34
the UK cohort study
45
and the CANAL effects of VWF, other proteins such as tumour necrosis factor (TNF)-α
study
46
– and one is prospective – the GTH PUP Study.
30
The French or transforming growth factor (TGF)-β, which may be present in
cohort study retrospectively evaluated 148 PUPs with severe plasmatic but not in recombinant products, may have protective or
haemophilia A, 62 of whom received a pdFVIII product stabilised by immune-modulating effects.
30
von Willebrand factor (VWF) and 86 of whom received a full-length
rFVIII concentrate. Under comparable treatment regimens and Immune Tolerance Induction
regardless of other risk factors, 11% of the patients receiving pdFVIII The treatment of patients with inhibitors is challenging. Particularly for
and 31% of those receiving rFVIII developed an inhibitor (p=0.049). those patients with high-responding inhibitors (>5 Bethesda units [BU]),
The UK cohort study retrospectively evaluated 348 children with severe prophylactic treatment with FVIII is impossible, and even after the
haemophilia A. All of them had more than 50 EDs. Information on the introduction of bypassing agents – mainly activated prothrombin
product used for initial management was available for 304 of them. complex concentrates (aPCCs) and recombinant activated factor VII
Inhibitors developed in 27% (47/172) of those PUPs initially treated (rFVIIa) – severe bleedings may be difficult to control. Because morbidity,
with rFVIII and in 14% (18/132) of those treated with pdFVIII mortality and treatment costs are high,
1,51
the ultimate goal of inhibitor
(p=0.009).
45
The recently published multicentre CANAL study, which treatment is to permanently eradicate the FVIII antibody and to restore
retrospectively documented treatment details of 316 PUPs with severe normal prophylactic treatment. The only proven way to achieve this goal
haemophilia A born between 1990 and 2000, did not find a significant is to induce immune tolerance to FVIII.
52,53
Different protocols for ITI
difference between the two product types. However, it must be have been developed: long-term high-dose FVIII treatment
mentioned that this study looked only for so-called ‘clinically relevant (Bonn/Frankfurt protocol),
54
long-term low-dose FVIII treatment (Van-
inhibitors’, excluded 15 inhibitors that were by definition of the study Creveld protocol)
55
or combined treatment with several extracorporeal
protocol not seen as clinically relevant, did not require regular or immune adsorptions, immune suppression with cyclophosphamide,
frequent inhibitor testing, did not repeat any inhibitor measurements intravenous gammaglobulins and high-dose FVIII (Malmö protocol).
56
EUROPEAN HAEMATOLOGY 17
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