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Inhibitor development

factor is impossible. Those with persistent high-titer inhibitors are at a particularly increased risk of developing target joints, severe arthropathy and a diminished physical quality of life.5

In the past,

inhibitor development doubled the mortality rate of severe haemophilia patients. Over recent years, it has improved and is now identical in patients with and without inhibitors.2

Inhibitor eradication can be achieved by immune tolerance therapy, in which FVIII product is regularly administrated (daily to three times a week), with the aim of tolerising the immune system. However, 10 to 40% of patients do not achieve immune tolerance.6

The economic

burden of the management of patients with persistent inhibitors is one of the highest of that for any chronic disease, estimated to average €18,000 per month.5 In haemophilia B and in mild and moderate haemophilia, inhibitors occur less frequently than in severe haemophilia A (1 to 3% for haemophilia B and 3–13% for mild/moderate haemophilia A). In patients with mild or moderate haemophilia, inhibitors can also cross- react with endogenous FVIII, resulting in a more severe phenotype with spontaneous bleeding.

Risk factors for inhibitor development Knowledge of the genetic and environmental determinants of the risk of inhibitor development contributes to the prediction of patients’ individual risks of developing inhibitors. Determinants of inhibitor development have been most extensively studied in severe haemophilia A patients because the most inhibitors occur in patients with severe haemophilia. In patients with mild or moderate haemophilia A or haemophilia B, the F8 and F9 genotype has been reported to be an important determinant of inhibitor development. Specific F8 mutations that alter the three-dimensional structure of the FVIII protein are associated with a higher incidence of inhibitor formation (for example, Arg593Cys and Arg2150His).7

Risk factors for inhibitor development in severe haemophilia A Risk factors are summarised in Figure 1.

Genetic determinants (a) F8 genotype


In severe haemophilia A the causative F8 genotype is the most important genetic risk factor for inhibitor development.8 The quantity and size of the F8 gene

product that can potentially be produced determine the degree of central immune tolerance towards infused FVIII. Compared with the risk of inhibitor development in patients with intron 22 inversions, the risk of patients with large deletions and nonsense mutations is higher (pooled OR 3.6; 95% CI, 2.3–5.7 and OR 1.4; 95% CI, 1.1–1.8, respectively), the risk of patients with intron 1 inversions and splice-site mutations is equal (pooled OR 0.9; 95% CI, 0.6–1.5 and OR 1.0; 95% CI, 0.6–1.5, respectively), and the risk of patients with small deletions and insertions and missense mutations is lower (pooled OR 0.5; 95% CI, 0.4–0.6 and 0.3; 95% CI, 0.2–0.4, respectively). Further subclassifications in type and location of F8 mutations have been demonstrated to carry specific inhibitor risks.8

3.2-times higher risk of inhibitor development (95% confidence interval (CI), 2.1 to 4.9).13

A mismatch between the FVIII molecule haplotype in four nonsynonymous single-nucleotide polymorphisms in recombinant FVIII products and the FVIII haplotypes prevalent among black patients with haemophilia has been suggested as a cause of the increased inhibitor risk observed in black patients.14

(d) Ethnicity Several studies recognised that haemophilia patients of African American and Latin American descent were at a twice higher risk of inhibitor development than patients of caucasian descent.13

studies did not corroborate this finding.15

However, other

“Knowledge of the genetic and environmental determinants of the risk of inhibitor development contributes to the prediction of patients’ individual risks of developing inhibitors”

(b) HLA genotype

Human leucocyte antigen (HLA) class II molecules are transmembrane proteins on antigen-presenting cells involved in the presentation of extracellular antigens. An individual’s HLA class II phenotype determines which, if any, FVIII-derived peptides are presented to T lymphocytes and thereby whether an immune response is initiated.9


class I alleles A3, B7, and C7 and HLA class II alleles DQA0102, DQB0602, and DR15 were weakly associated with a higher risk of inhibitor development [relative risk (RR), 1.9 to 4.0], whereas the HLA C2, DQA0103, DQB0603, and DR13 alleles were suggested to be protective against inhibitor development (RR, 0.1 to 0.2).10,11 However, several other studies reported associations with various other HLA alleles or did not find any association between HLA type and inhibitor development.12

(c) Family history

The important role of genetic risk factors was first acknowledged in studies that found a higher concordance rate of inhibitors in siblings than could be expected from a random occurrence. A positive family history of inhibitors has been reported to be associated with a

(e) Polymorphisms in immune response genes

Polymorphisms in genes involved in the regulation of the immune system (TNFα, CTLA-4, Il-10) have been associated with the risk of developing inhibitors.12,16,17

An evaluation of 13,331

SNPs in immune response and immune modifier genes in 833 patients yielded 53 SNPs that were predictive of the inhibitor status. Of these, 13 markers were statistically significantly, associated with inhibitor development in different patient cohorts. The identified genetic markers are known to be involved in various B and T cell- mediated mechanisms and intracellular signalling pathways.18

The clinical

importance of the identified markers still needs further clarification.

Non-genetic determinants In addition to genetic determinants, observations of discordant inhibitor status in monozygotic twins suggest that environmental risk factors also play a role in the development of inhibitors.13

On a

susceptible genetic background, determined by the F8 genotype, HLA class II genotype and polymorphisms in immune regulating genes, non-genetic risk factors modify the risk of inhibitor development.

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