Successful low dose immune tolerance induction in severe haemophilia A with inhibitors below 40 Bethesda Units.

Different regimens are used to achieve immune tolerance in patients with severe haemophilia A and inhibitory allo-antibodies against factor VIII (FVIII). In this study, results of 26 years of low dose immune tolerance induction are evaluated. We evaluated 21 patients, who were treated with regular infusions of low dose FVIII (25-50 IU kg(-1) every other day or three times a week) to obtain immune tolerance. Several risk factors for success rate and time to success were analysed. In 18 of 21 patients (86%) immune tolerance induction (ITI) was successful. The median of the maximum inhibitor titre before start of ITI was 4.5 BU mL(-1). Success rate was associated with both a pre-ITI titre and a maximum titre during ITI below 40 BU mL(-1) (P = 0.003). The time to success was significantly shorter if the maximum inhibitor level during ITI was below 40 BU mL(-1) (P = 0.040). In low titre inhibitors (<5 BU mL(-1)) this effect was even stronger (P = 0.033). Low dose immune tolerance induction therapy was successful in severe haemophilia A patients with a pre-ITI titre below 40 BU mL(-1). The time to success is predicted by a maximum ITI titre below 40 BU mL(-1), and is even shorter in low titre inhibitors (<5 BU mL(-1)). We suggest that all patients with severe haemophilia A and a pre-ITI inhibitor titre below 5 BU mL(-1), should be treated with low dose immune tolerance induction therapy. Patients with a maximum titre below 40 BU mL(-1) may also strongly benefit from the beneficial effects of low dose immune tolerance induction therapy.

Discordant antibody response in monozygotic twins with severe haemophilia A caused by intensive treatment.

Both genetic factors and environmental factors are suggested to play a role in the aetiology of inhibitor development in patients with severe haemophilia A. Monozygotic twins are ideal candidates to study the influence of environmental factors. We describe a pair of 3-year-old monozygotic twin brothers with severe haemophilia A. Prenatal diagnosis confirmed the presence of an intron 22 inversion. Other patient-related factors such as birth weight, vaccinations and the duration of breastfeeding were similar. At the age of 7 months, one boy suffered from a spontaneous subdural haematoma, which needed complete correction of haemostasis with continuous infusion of a third-generation recombinant factor VIII. A persistent high-titre inhibitor with severe clinical symptoms developed, that could only be eradicated with high-dose immune tolerance induction (ITI) for 36 months in combination with rituximab therapy. His twin brother first received treatment at 9 months of age with the same FVIII product. After treatment on nine exposure days, he developed a low-titre inhibitor at the age of 14.5 months. Unlike his brother, he was tolerized without difficulties with low-dose ITI within 2 months. The discordant antibody responses were underlined by dissimilar IgG1 and IgG4 levels in their plasma. The discordant immune response to FVIII in this pair of monozygotic twin brothers seemed to be related to intensity of treatment and severity of bleeds. This confirms that these environmental factors play an additional role in the development of inhibitors.

Risk stratification for inhibitor development at first treatment for severe hemophilia A: a tool for clinical practice.

BACKGROUND: Replacement therapy in severe hemophilia A patients is complicated by formation of inhibitory antibodies against factor VIII (inhibitors) in around 25% of children. Management of bleeds and eradicating inhibitors is complicated, costly and not always successful. OBJECTIVE: To develop a simple score that stratifies untreated patients with severe hemophilia according to their risk of developing inhibitory antibodies. METHODS: The study population consisted of 332 children, with severe hemophilia A, selected from a retrospective multicentre cohort (the CANAL study). The score was based on risk factors available at the first treatment episode. The score was validated in an external population. RESULTS: A total of 87 patients (25%) developed inhibitory antibodies. The selected risk score comprised positive family history (two points), high risk factor VIII gene mutations (two points), and intensive treatment at initial treatment (three points). Inhibitor incidence was 6% (six of 95) in patients without risk factor, 23% (38 of 170) in those with two points, and 57% (38 of 67) in patients with three points or more. The discriminative ability of the score was good (area under the receiver operating curve 0.74). The score performed equally well in the external validation population. CONCLUSION: These findings suggest that the development of inhibitory antibodies in untreated patients with severe hemophilia A can validly be predicted with the presented risk stratification score.

[Haemolytic anaemia and a clotting disorder as first signs of cystic fibrosis in two infants]. / Hemolytische anemie en een stollingsstoornis als eerste manifestatie van cystische fibrose bij twee zuigelingen.

2 infants, a boy aged 8 weeks and a girl aged 5 months, presented with symptoms of fat-soluble vitamin deficiencies. The first infant had frequently voluminous bowel movements, anaemia and was not thriving; he had anaemia due to vitamin-E deficiency. The second infant had multiple haematomas on the trunk and legs due to a vitamin-K deficiency-related clotting disorder. The sweat test was positive in both cases, confirming the diagnosis of cystic fibrosis. The infants were treated with supplementary pancreatic enzymes and fat-soluble vitamins A, D, E and K. Cystic fibrosis rarely presents with symptoms of fat-soluble vitamin deficiency. However, in cases of unexplained haemolytic anaemia or haemorrhagic disorder due to vitamin E or K deficiencies, respectively, cystic fibrosis should be considered as a possible cause.