To establish the pharmacokinetic profile of activated recombinant coagulation factor VII (rFVIIa; NovoSeven in children with haemophilia A, and to compare it with the pharmacokinetic profile in adults with haemophilia A. Twelve children (2-12 years) received one single dose of rFVIIa 90 and 180 micrograms kg(-1) in randomized order separated by a washout period of 48 h to 1 month. Six adults (18-55 years) received a single dose of rFVIIa 90 micrograms kg(-1). The pharmacokinetic analyses were based on a non-compartmental method. In children, the plasma level of FVII increased proportionally with the dose. The total body clearance normalized for body weight was significantly faster in children than in adults (FVII:C, 58 vs. 39 mL kg(-1) h(-1) and FVIIa, 78 vs. 53 mL kg(-1) h(-1), P < 0.05). A trend towards a larger volume of distribution at steady-state in children than in adults was observed (P > 0.05). Dose proportionality was established for plasma concentrations of FVII in children with haemophilia A at the dose levels investigated (90 and 180 micrograms kg(-1) rFVIIa). Following administration of rFVIIa 90 micrograms kg(-1), significantly faster clearance was observed in children compared with adults, suggesting that higher doses of rFVIIa may be needed to achieve the same plasma levels as in adults.

Haemophilia A is a common disorder of blood coagulation caused by a deficiency of factor VIII. It is inherited as an X-linked recessive trait, and one-third of all cases are thought to result from de novo mutations. The clinical severity of haemophilia A varies markedly among different families and a subset of the patients with severe disease develop antibodies against factor VIII, called inhibitors. Because of this heterogeneity, it is likely that many different molecular lesions result in haemophilia A. Indeed, of the nine mutations described to date, all appear to be unique changes. However in this study of 83 patients with haemophilia A we have identified two different point mutations, one in exon 18 and one in exon 22, that have recurred independently in unrelated families. Each mutation produces a nonsense codon by a change of CG to TG, and each occurred de novo on the X-chromosome donated by the maternal grandfather. These observations strongly support the view that CpG dinucleotides are mutation hotspots.

To evaluate joints alterations, we performed clinical examination, X-rays and magnetic resonance imaging (MRI) (Denver score) in 165 joints of 40 children with severe (n, 32) or moderate (n, 8) haemophilia A or B. All investigated joints had a history of more than three bleeds. At evaluation, 25 of 40 haemophilic patients were on prophylaxis for the last 1-8 years (mean: 3.5 years). MRI revealed chronic synovitis in 55.4% and 50% of joints, which were diagnosed, as normal by the clinical scale and plain radiography respectively. Moreover, MRI unmasked more profound alterations than those observed by plain radiography in 70% of cases. Statistical analysis showed that the clinical and Pettersson scores in contrast to the Denver score provide an underestimation of arthritic changes. Besides, Denver score did not provide resolution in differentiating stages of arthropathy, because of its inherent nature; however, a score of 6 expressing severe synovitis seemed to be the cut-off value for the distinction of severe cases. Based on MRI findings we intensified prophylaxis in nine children and initiated it in another nine children. Five children, who were already on prophylaxis complied with our recommendations and eliminated haemorrhages. Finally, three boys with severe haemophilic arthropathy in knees underwent successful chemical synovectomy with rifampicin.

Background: The pathogenesis of thrombosis in childhood seems to be multifactorial implicating genetic and environmental factors. Aim: To compare the distributions of mutations/polymorphisms in genes affecting hemostasis (factor V Leiden – FVL, FV H1298R-FVR2, FII 20210A, b-Fib 455G>A, FXIII V34L, PAI-1 4G, HPA-1b) or homocysteine metabolism (MTHFR C677T, MTHFR A1298C) among 90 children with arterial ischemic stroke (AIS) and 103 controls, and to associate the carriage of these mutations/polymorphisms with their corresponding proteins in children with AIS. Results: AIS was more frequent in boys (p < 0.01). No studied mutation/polymorphism was found to be a risk factor for AIS, except for FVL [odds ratio 4.2 (95% CI 1.5–12.1)], the presence of which was even higher in 31 children with congenital AIS [odds ratio 6.82 (95% CI 2.0–22.8)]. FVL carriers had an odds ratio of 5.76 (95% CI 1.6–6.4) when FVR2 was absent. In thrombosed children, activated protein C resistance, prothrombin and fibrinogen levels were higher in the presence of FVL, FII20210A or b-Fib 455G→A, respectively. Double heterozygotes in both MTHFR C677T and A1298T or homozygotes in one had significantly elevated homocysteine levels. Conclusion: Except for FVL, no definite conclusion could be reached regarding the involvement of the studied mutations/polymorphisms in childhood AIS.

Arthropathy is considered as an irreversible and progressive complication in patients with haemophilia, even in children on prophylaxis. To estimate the progression of haemophilic arthropathy, 85 joints of 24 boys with severe (n = 18) and moderate (n = 6) haemophilia (A: 22, B: 2) were investigated with clinical examination, X-rays and magnetic resonance imaging (MRI) at two time periods (time 0 and 1). Patients' age at time 0 was 10.5 +/- 3.6 years and time elapsed to time 1 was 3.8 +/- 1.4 years. At time 0: all investigated joints had more than three bleeds. Sixteen boys were on secondary prophylaxis for 5.4 +/- 2.8 years. Clinical score (a modification of World Federation of Haemophilia's scale): 2.0 +/- 3.6, X-ray score (Pettersson): 2.1 +/- 2.8, MRI score (Denver): 4.5 +/- 3.8. After the first evaluation, prophylaxis was intensified in 11 children and initiated in four. At time 1: clinical score: 1.5 +/- 3.1, X-ray: 1.7 +/- 2.7, MRI score: 5.1 +/- 4.1. On average, the clinical and X-ray scores showed a significant improvement (26% and 40% of the joints respectively, P < 0.01) and the number of haemarthroses evidenced a threefold reduction from time 0 to 1 (P < 0.01), findings that could be associated with the modification of prophylaxis after time 0. MRI findings showed deterioration in 34% of the joints. Conversely, 14 joints (16.5%) with mild or moderate synovitis without cartilage degradation at time 0 showed an improvement at time 1. The information carried by the three scales could be divided into information shared by the three scores and information specific to each score, thus giving a more complete picture of joint damage caused by bleedings.