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Haemophilia A (HA) is caused by a lack or reduced amount of factor VIII protein (FVIII). About one-third of patients with non-severe HA carrying specific missense mutations show discrepant results between FVIII activity (FVIII:C), measured by one-stage or chromogenic two-stage assays. The aim of this study was to elucidate the mechanism underlying the assay discrepancy in vitro and in silico. Thirteen missense mutations in the Factor 8-gene associated with discrepant results in patients were transiently expressed. FVIII:C of the mutations was determined using two one-stage assays (FVIII:C1st, FVIII:CBonn) and a two-stage chromogenic assay (FVIII:Cchr). Furthermore, thrombin generation test (TGT) and in silico analysis were performed to investigate the haemostatic potential as well as the structural impact of the variants, respectively. For the majority (9/13) of the analysed mutations, the discrepancy was confirmed. Moreover, we established a modified TGT protocol for in vitro characterization of FVIII. Hence, TGT parameters were significantly impaired in the group of variants associated with higher chromogenic values. Additionally, in silico analysis revealed the impact of the mutations on FVIII protein structure leading to assay discrepancy. Moreover, the data shows that also among one-stage clotting assays, assay discrepancy is observed. Our results show that for the majority of mutations, application of a global assay like TGT method could help to improve diagnosis or correct assessment of the severity of HA.

Primary prophylaxis is a method of haemostatic management to prevent bleeding and arthropathy in patients with severe haemophilia. The aim of this study was to evaluate the usefulness of primary prophylaxis in patients with severe haemophilia A. This study included 15 patients with haemophilia A who received primary prophylaxis at our institution for a minimum of 5 years. We evaluated the annualized bleeding ratio of joints or other sites, current joint function, and X-ray images and MRI scans taken when patients were 6 years old. The range of patients' ages at the end of the study was 6.2-16.8 years, and at the start of primary prophylaxis it was 0.8-2.4 years. Factor VIII concentrates (25-40 units kg(-1) dose(-1)) were administered 3 times/week or every other day, according to the Swedish protocol. Mean joint and non-joint annualized bleeding ratios were 0.49 ± 0.5 and 1.54 ± 1.69, respectively. At the final evaluation, all patients displayed a normal range of motion for both elbows, knees, and ankles. The radiography and MRI findings at the age of 6 were unremarkable in all patients. Overall, primary prophylaxis for patients with severe haemophilia A was performed safely, reduced the number of bleeding events, and prevented progression to arthropathy.

Objective The aim of this study was to assess the consumption of anti-haemophilic drugs by adults and children with severe haemophilia A or B (residual activity of FVIII or FIX ≤2%) and to quantify the average direct medical costs. Method A retrospective multicentre cost-of-illness study from the perspective of French national health insurance system. The costs include only the use of clotting factors. Main outcome measure Consumption was expressed in UI/kg/year and costs in euros/kg/year. Results From January 1, 2001 to December 31, 2002, data from 81 adults and 30 children with severe haemophilia A (n = 92) or B (n = 19) and included in the “SNH” were collected and analysed. A coagulation factor inhibitor was present in 10 patients (9%). Four of them were high responders. Mean age and body weight were respectively 28 ± 17 years and 58 ± 24 kg. Except for one adult patient, all (99%) had outpatient treatment, 44 patients (40%) were hospitalized and treated by recombinant or/and plasma-derived FVIII or FIX or/and rFVIIa. Overall median annual consumption of anti-haemophilic drugs per patient was estimated at 1,333 UI/kg, with a median cost-of-illness of 1,156 euros/kg. Patients with severe haemophilia B consumed more than patients with severe haemophilia A, though not significantly (P = 0.096), with a median of 2,167 vs. 1,100 UI/kg/year and a median cost of 1,760 vs. 917 euros/kg/year (P = 0.13). Children consumed respectively more than adults (P = 0.008), with a median of 3,204 vs. 1,106 UI/kg/year and a median cost of 2,614 vs. 913 euros/kg/year (P = 0.012). The median cost for patients with an inhibitor was 3,291 euros/kg/year, approximately threefold higher than that of patients without an inhibitor (926 euros/kg/year) (P = 0.022). Conclusion It suggests a higher consumption and cost of anti-haemophilic drugs among children when compared to adults. Haemophilia B patients did not consume significantly more than haemophilia A patients, whereas the consumption and cost for patients with or without inhibitors differed significantly.

This report describes the case of a boy with severe haemophilia A and factor VIII inhibitor who suffered subarachnoid haemorrhage at age 7 years, followed by bleeding in the right cerebellar hemisphere and an epidural haematoma at age 12 years. The patient received intensive replacement treatment leading to reversal of neurological signs and symptoms and resorption of haematomas, as demonstrated by CT scans.

In spite of the modern day innovations, managing severe Haemophilia patients with inhibitors continues to be a challenge. The management of patients with severe haemophilia with inhibitors who are undergoing major surgeries like open heart surgery is technically demanding, fraught with peri-operative complications and needs a multidisciplinary approach. We describe a young man with severe haemophilia with low titre inhibitors who underwent a successful open heart surgery and aortic valve replacement, supported only with bolus doses of Factor VIII and tranexamic acid without any complications.

Carrier detection tests were carried out on 21 mothers of isolated cases of severe Haemophilia A, according to WHO recommendations. A maximum likelihood estimate of the male to female mutation ratio of 9.6 (95% confidence limits 2.2-41.5) was obtained.