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Coagulation Disorders Haemophilia
Risk of Inhibitor Development in Children with Haemophilia A
a report by
Marijke van den Berg
Board of Directors, Meander Medical Centre, Amersfoort
The development of inhibitors in children with haemophilia A presents a A and intron 22 inversion showed an inhibitor concordance rate of only
major problem in terms of both the success and the cost of treatment.
1
40%. Moreover, the concordance rate for the presence of inhibitors
Inhibitors develop in response to treatment with factor VIII (FVIII), which is among inhibitor families was only 42.4%. Data from two large registries
administered to haemophilia A patients to overcome bleeding episodes. of unrelated patients with haemophilia – the Haemophilia A Mutation,
The risk of inhibitor development is highly dependent on disease severity: Structure, Test and Resource Site (HAMSTeRS) and Bonn databases –
it is estimated that between 20 and 52% of patients with severe predicted a concordance among inhibitor families of 20%. The
haemophilia A develop inhibitors compared with approximately 3% of differences between the MIBS study and the HAMSTeRS and Bonn
those with mild to moderate disease.
2–9
For the most part, inhibitors databases suggest that the risk of inhibitor development may involve
develop early in a patient’s treatment life – usually after nine to 12 days of other factors beyond the FVIII genotype alone.
exposure to FVIII.
10
Subsequent to inhibitor development, bleeds are
treated with bypassing agents, which are less efficient and more expensive Indeed, recent evidence points to defects related to the FVIII immune
than FVIII replacement. Immune tolerance induction (ITI) therapy is used response genes. Major histocompatibility complex (MHC) molecules,
successfully in approximately 70% of haemophilia patients to eradicate which play a central role in the cellular cascade leading to antibody
inhibitors and allow future treatment with exogenous FVIII.
11
Future formation, have been evaluated as potential co-determinants. Two
studies aim to further optimise the ITI treatment regimen. Indeed, the risk studies detected a weak influence from MHC class I/II genotypes,
22,23
of inhibitor development is much greater and more frequent in previously although no association was found in the MIBS cohort.
24
The MIBS study
untreated patients, while it is rarer in previously treated patients. In this also showed that there was a strong association between inhibitor
latter group, inhibitor risk factors are thought to be more treatment- development and a polymorphism located in the promoter region of the
related and in previously treated patients with >150 exposure days to FVIII IL-10 gene. Patients with this IL-10 genotype had a significantly greater
are considered low-risk.
12
risk of developing an inhibitor compared with patients with other IL-10
genotypes.
25
A genetic predisposition to the development of FVIII
Alongside disease severity, numerous patient-determined factors have inhibitors is evident; however, further studies are required.
been demonstrated to alter the risk of inhibitor development in
haemophilia A patients. These include a family history of inhibitor Ethnic Background
development, FVIII gene mutations, ethnicity, prophylaxis treatment, the Inhibitor incidence is high in African-American, Hispanic and Latin
intensity of treatment and the individual FVIII concentrate.
7,9,12–17
Age at haemophilia patients compared with Caucasian patients.
14
This is
first exposure
14,18
has also been proposed as a potential risk factor for thought to be due to immunogenotypic factors carried in these racial
inhibitor development, although the relative importance of this groups. Two prospective trials have reported that African-Americans are
treatment-related factor is now questioned.
15,18,19
twice as likely to develop inhibitors compared with Caucasians, despite
a similar level of haemophilia in both ethnic groups.
3,26
These results
Genetic Risk Factors suggest a racial risk and hence a genetic risk for the development of
Severe defects, such as large deletions in the FVIII gene, inversions inhibitors in haemophilia A.
(particularly intron 22 inversion) and stop mutations, are associated with
a higher risk of inhibitor development than small deletions/insertions, Intensity of Factor VIII Treatment
missense mutations or splice site mutations.
7,13,18,20,21
In a recent study of In 1970, it was suggested that less frequent exposure to FVIII concentrate
children with severe haemophilia A who were first exposed to FVIII as in patients with mild haemophilia accounted for a lower incidence of
neonates, 41 of 141 children with severe genetic defects (29%) inhibitor development.
27
However, the cumulative FVIII exposure was
developed inhibitors compared with 12 of 90 children with non-severe found to be no higher in patients with severe haemophilia who
defects (13%; p=0.006).
7
Similarly, in the Concerted Action on developed inhibitors than in those without inhibitors.
28
In the CANAL
Neutralizing Antibodies in severe haemophilia A (CANAL) cohort study, cohort study, a dose of 35–50IU/kg over five consecutive days was
patients with severe defects were nearly three times more likely to associated with 1.4 times the risk than a normal dose (<35IU/kg). This
develop inhibitors compared with patients with low-risk mutations.
18
increased to 3.3 times the risk of a normal dose when FVIII was
administered at doses of ≥50IU/kg.
18
The Malmö International Brother Study (MIBS), a large-scale family study,
examined the shared host genetic factors between brothers with severe The association between inhibitor development and number of
haemophilia A and found a 70% concordance in terms of the presence exposure days to FVIII was also examined in the CANAL cohort study.
18
or absence of inhibitors.
13
In the study, siblings with severe haemophilia It was reported that a higher number of consecutive exposure days
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