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Inhibitor development

(a) Intensity of FVIII treatment The intensity of treatment, ranging from high-dose intensive FVIII (FVIII) treatment to prophylactic treatment, has been associated with the inhibitor incidence.19–22

Intensive treatment with

high-dosed FVIII treatment for bleeds and surgery has been associated with an increased risk of inhibitor development. On the other hand, low-intensity treatment, low-dose, prophylactic FVIII treatment was associated with a decreased risk for inhibitor development. It has been suggested that the effect of prophylaxis was more pronounced in patients with low-risk F8 gene mutations, but diminished in patients with high-risk F8 gene mutations.20

The extent of tissue damage during FVIII treatment is related to the risk of inhibitor development. During intensive treatment with FVIII for major bleeds or surgery, extensive tissue damage and inflammation are often present. The injured cells release endogenous cellular alarm signals that activate antigen presenting cells. These cells present FVIII-derived antigen with up-regulated costimulatory signals to T lymphocytes. These cells then provide help to enhance antibody formation by B lymphocytes. In prophylactic treatment, opposite treatment conditions are present; patients are exposed to FVIII in the absence of tissue damage. The presentation of FVIII antigen in combination with costimulatory signals is prevented. Therefore, in prophylaxis, immune tolerance is more likely to result.23

(b) FVIII product type

Ever since their introduction, there has been concern that recombinant FVIII products carry an increased risk of inhibitor formation. Post-translational modifications of the FVIII protein, lack of von Willebrand factor or other plasma compounds (such as transforming growth factor β) and changes in phospholipid binding affinity have been suggested to be responsible for an increased immunogenicity of recombinant FVIII products.24–26

assessed the available data, but there is no conclusive evidence for a difference in immunogenicity between recombinant FVIII products and plasma-derived products.3,27,28

Currently ongoing is a trial

randomising patients with severe haemophilia A to either any plasma- derived von Willebrand factor containing FVIII products (with a ratio of VWF to

FVIII:C of ≥0.3) or second- or third- generation recombinant FVIII products.29 From the point of view of inhibitor development, plasma-derived FVIII products are not preferred over recombinant FVIII products. Although in the past 20 years no transmission of blood-transmitted hepatitis viruses or HIV has occurred, a theoretical risk exists of transmission of prion protein of the variant Creutzfeldt Jakob disease. Therefore, from a safety point of view, even though international guidelines do not express a preference for recombinant over plasma-derived FVIII products, several national guidelines recommend

FVIII product type Intensity of FVIII treatment

Infections & vaccinations Mode of infusion


Family history of inhibitors F8 gene mutation type MHC II phenotype

Polymorphisms cytokine genes Figure 1: Putative genetic and non-genetic risk factors of inhibitor development in severe haemophilia A

immunogenic products. New developments in haemophilia treatment emerge fast, including the use of novel technologies in clotting factor product manufacture. Recently introduced FVIII products with longer half-lives still have an unknown immunogenicity. Furthermore, in the future, alternative therapies to intravenous infusions of FVIII products may be adopted, such as oral administration of FVIII DNA,34 bispecific antibody therapy to restore FVIII cofactor activity,35

premature termination

codon-suppressing therapeutics36 therapy.37

and gene Also, these future therapies may

give rise to inhibitory antibodies. However, it is difficult to predict their effects on the

“A risk score was developed that can be used to classify previously untreated patients with severe haemophilia according to their risk of inhibitor development”

the use of recombinant FVIII products.1,30 Differential risks of inhibitor

development between recombinant FVIII products have been reported. Two highly immunogenic pasteurised plasma-derived FVIII concentrates gave rise to high-titer inhibitors in patients who had been treated extensively with FVIII.31,32

One Three reviews systematically

study reported a 60% increased risk of inhibitor development (CI 1.08-2.37) with second generation full-length recombinant FVIII products compared to third generation full-length recombinant FVIII products, which needs further confirmation.33


findings may provide the opportunity to gain knowledge on specific reasons for increased immunogenicity, which could help the further development of new less

incidence of inhibitor development. It is therefore of utmost importance to continually monitor the effect of new treatments on the risk of inhibitor development.

Prediction score

A risk score was developed to classify previously untreated patients with severe haemophilia according to their risk of inhibitor development.38

The risk score

comprised positive family history (two points), high risk F8 gene mutations (two points), and intensive treatment at initial treatment (three points). The

development of inhibitors could validly be predicted with the risk stratification score. The prediction score will be 19

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