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Immunological Aspects of Inhibitor Development in Haemophilia
data from trials with sucrose-formulated full-length recombinant FVIII FVIII activity dropping below 1%.
77
Some patients can exhibit
reconstituted in an aqueous solution of pegylated liposomes (BAY 79- particularly severe bleeds that are often life-threatening, with large
4980) in treatment-experienced patients have not shown any cases of ecchymoses, muscle bleeds and gastrointestinal or urogenital
inhibitor development to date.
67–70
However, none of these studies was bleeding.
20
Natural history studies of inhibitors in mild or moderate
designed or powered to look at inhibitors appropriately. haemophilia have been unable to establish any definitive method of
resolving the presence of inhibitors; inhibitors have been found to
Early prophylaxis has been associated with a significantly lower disappear spontaneously or following immune tolerance induction,
incidence of inhibitors compared with episodic treatment.
52,71
It has while persisting in some patients after a median follow-up of 99
been suggested that FVIII infusions in the absence of immunological
danger signals, as in prophylaxis, may inhibit the immune response via
peripheral anergy of FVIII-specific T lymphocytes.
72
Other conditions
The effect of treatment intensity on the
that trigger the immune system and regulate immunomodulatory
risk of inhibitor development continues
elements have been proposed to facilitate inhibitor development. Such
factors include severe infectious diseases, vaccinations and
to be debated; the impact of continuous
immunisations that occur in close proximity to the initial infusion
infusion on the immune system is not
of factor concentrates, as well as surgical procedures and traumatic
clear, and more data are needed.
tissue damage that may lead to the exposure of large quantities of
potential immunological danger factors. These events can challenge
and activate the immune system, modifying the level of cytokines months.
20
The aetiology of these late inhibitors appears to differ from
and immune-regulatory molecules, thereby influencing the immune that of inhibitors that arise earlier in life; while the appearance of
response to the infused protein and promoting the formation inhibitors in the initial days of factor replacement therapy suggests
of antibodies. primary intolerance to a foreign antigen, late acquisition of inhibitors
after hundreds of treatment days suggests a breakdown of tolerance
Studies have shown contrasting results regarding this hypothesis; in patients previously tolerant to treatment.
78
while patients with a low risk of developing inhibitors (e.g. those with
mild haemophilia) have developed inhibitors post-operatively in Intensive exposure to FVIII has also been established as a risk factor for
response to FVIII exposure,
73
other studies have shown no association the development of inhibitors, where patients who develop an inhibitor
between infections, vaccinations, surgery or central nervous system following continuous infusion exhibited the typical risk profile for
bleeding and an increased frequency of inhibitors.
50
These results are inhibitor formation: severe haemophilia A with a severe gene defect and
indicative of a need for further study. fewer than 50 factor replacement exposure days.
79
Notably, patients with
mild haemophilia are particularly susceptible to inhibitor development in
Interestingly enough, inhibitors that develop in haemophilia patients response to intensive treatment; studies suggest that a continuous
infected with HIV frequently resolve on their own if cellular infusion of FVIII confers a higher risk of inhibitor development than bolus
immunodeficiency is advanced,
74
and until recently the development infusions.
73,79
In fact, patients with mild haemophilia may receive more
of new inhibitors against FVIII in severely immunodeficient HIV- intensive treatment, as the continuous infusion doses are comparable, if
infected haemophilia patients had never been reported. One case not higher, than the commonly used doses in patients with severe
study examined a 56-year-old male with severe haemophilia A who haemophilia.
73,80,81
Some centres therefore opt to avoid continuous factor
initiated highly active antiretroviral therapy (HAART) in 1997 and infusion in patients with mild haemophilia.
79
maintained undetectable viral loads between 1997 and 2001;
inhibitors were undetected prior to 2001.
75
It is suggested that HAART Uncomplicated venous access is an essential element of factor
in severely immunodeficient patients can cause immune reconstitution replacement therapy. Prophylactic infusions are usually administered
inflammatory syndrome (IRIS), which can manifest as immune three times per week in patients with haemophilia A and twice per
restoration and result in the spontaneous development of antibodies week in those with haemophilia B. In the ideal scenario, prophylaxis
against FVIII. In this particular case, the loss of tolerance against FVIII would be initiated at an early age, providing parents with the
was not associated with any concurrent opportunistic infection, convenience of administering the factor concentrate in the home
vaccination, surgery, trauma or switch of FVIII product. The authors of setting, but this is often difficult in the peripheral veins of small
the study recommend that immunodeficient haemophilia A patients children. Episodic treatment would also require safe and easy access to
receiving HAART undergo regular screening for FVIII inhibitors, as the veins for the immediate administration of factor concentrate in the
incidence of novel inhibitors may be underestimated. case of a bleeding episode.
The severity of the disease can also influence the management of the Central venous access devices (CVADs) facilitate treatment of young
disease. Although the incidence of inhibitors is highest in patients with children with problematic peripheral venous access, and are commonly
severe haemophilia, the less common development of inhibitors in used to allow parents to manage home treatment at an early age.
patients with mild (baseline FVIII level 5–30% of normal) or moderate However, infection is a frequent complication of CVADs, with rates
haemophilia occurs in the second or third decades of life or later; such ranging from 0.14 per 1,000 patient-days to 4.3 per 1,000 patient-
patients exhibit greater variability in their bleeding phenotype.
76
The days.
82–87
Notably, infection occurs in a greater frequency in patients
bleeding pattern may become similar to that of patients with severe with inhibitors;
85–87
a review of various studies has found that 50–83%
haemophilia, with severe spontaneous joint and muscle bleeds and of patients with inhibitors are prone to infection.
88
Possible
EUROPEAN HAEMATOLOGY 31
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