Inherited factor VII (FVII) deficiency is a rare autosomal disorder characterized by a weak relationship between FVII activity (FVII:C) and operative bleeding risk. We report a retrospective study of ...17 patients with a FVII:C below 0·1 IU/ml, in whom surgery was performed without any replacement therapy. Clinical and biological data were analysed to establish predictive criteria for bleeding tendency. We found that systematic preoperative replacement therapy may not be necessary for ‘minor’ surgical procedures, for patients suffering from inherited FVII deficiency, unless the clinical history includes severe haemorrhagic symptoms such as haemarthrosis, severe haematomas (even of soft tissue) or abundant epistaxis.
Summary
Factor XI (FXI)‐deficient patients may develop excessive bleeding after trauma or surgery. Replacement therapy should be considered in high‐risk situations, especially when FXI levels are ...below 20 IU dL−1. HEMOLEVEN is a human plasma‐derived factor XI concentrate available in France since 1992, but there are few data regarding its use by physicians. This prospective study assessed the use, efficacy and safety of HEMOLEVEN in common clinical practice. HEMOLEVEN was evaluated in FXI‐deficient patients in 13 French centres in a 3‐year postmarketing study. Forty‐four patients (30 females, 14 males) received 67 treatments. The median age was 37 years (8 months–91 years). Basal FXI levels were <1 to 51 IU dL−1 (median: 5.5); 29 patients were severely FXI‐deficient (<20 IU dL−1). FXI was administered prophylactically before 43 surgical procedures, 10 invasive procedures, 8 vaginal deliveries, or as curative treatment for six bleeds. The efficacy was assessed as excellent/good in 63, moderate in two and undetermined in two treatments. Seven patients experienced seven adverse effects, including two rated as serious: one sudden massive pulmonary embolism with fatal outcome and one case of inhibitor to FXI. HEMOLEVEN is effective for bleeding prevention in FXI deficiency. However, considering the benefit/risk ratio observed in relation to dosage in this study; firstly, it should be used sparingly due to its potential prothrombotic effect; secondly, new prescription procedures should be defined to adapt the dosage, especially in patients with intrinsic and/or acquired risk factors for thrombosis.
Abstract Introduction The value and challenges of long-term prophylaxis (LTP) in adolescents and young adults need further characterisation. Aim To determine the proportions of adolescents and young ...adults with severe or moderately severe haemophilia in France under LTP and treatment on demand (OD). Methods Patients 15 to 25 years old with haemophilia A or B, factor VIII/IX ≤ 2% and no current inhibitor could be included if they had been under factor VIII/IX treatment at least 12 months and kept a treatment and bleeding diary. Results LTP was administered to 169/212 patients (79.7%) and OD treatment to 40/212 patients (18.9%). The most frequent reasons for initiating LTP were joint bleeding, target joints and frequent bleeds; whereas OD treatment was most often selected on the basis of mild bleeding phenotype or because of constraints on LTP. The mean annual bleed rate (ABR) in the OD group (6.33) was higher than in the LTP group (3.07, p < 0.001). Mean ABR did not differ significantly between age strata (15
–
18, > 18
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21 and > 21
–
25 years), but was significantly higher for patients with severe haemophilia (4.02) as compared to those with moderate haemophilia (1.97, p = 0.002). No significant difference was observed in mean ABR for joint bleeds between the LTP and OD groups. Physician reported LTP compliance was good or excellent in 97.0% of patients. Conclusion LTP is the predominant factor VIII/IX treatment among adolescents and young adults with severe or moderately severe haemophilia in France. LTP was associated with low ABR and high compliance.
A double blind randomized cross-over multi-center study has been conducted to compare the pharmacokinetic and coagulation activation markers of high-purity factor IX concentrate subjected to both ...solvent/ detergent (SD) treatment and 15 nm-filtration (FIX-SD-15) with the licensed product subjected only to solvent-detergent (FIX-SD). This filtration process allows the elimination of small particles, such as non-enveloped viruses (i.e., hepatitis A and parvovirus B19). Eleven severe hemophilia B patients (FIX coagulant activity <2 IU/dl) received one infusion of 60 IU/kg of FIX-SD and one infusion of 60 IU/kg of FIX-SD-15 at least at 10 days interval. Blood samples were obtained before and at various time up to 72 h after infusion. The decay curves of factor IX (FIX:C and FIX:Ag) were evaluated by a model independent method. Bioequivalence was found between the two concentrates using the Schuirmann test. The mean FIX:C and FIX:Ag recovery of FIX-SD-15 was 1.08 and 0.89 IU/dl/IU/kg respectively with a mean half-life of 33.3 h for FIX:C and 25.6 h for FIX:Ag. Six months after initial enrollment, pharmacokinetic parameters were similar in the 7 patients tested. There was no significant variation of prothrombin fragment 1+2 and thrombin-antithrombin complexes measured up to 6 h after infusion, indicating that there was no activation process after administration of FIX. In conclusion, these data demonstrate that the introduction of a 15 nm filtration does not alter the pharmacokinetic profile of a well characterized SD FIX concentrate while providing additional viral safety.
Fifteen previously untreated patients (Pups) with severe haemophilia B (factor IX activity < or = 2 U/dl) only treated with one brand of plasma-derived high purity factor IX concentrate (FIX LFB) ...were studied. Age at first injection varied from 1 to 137 months and follow-up since this first injection from 21 to 86 months (median: 35). Cumulative exposure days (CED) were from 4 to over 100 (median: 26). Among these 15 Pups only one developed an inhibitor. Mutation analysis performed in all patients showed total gene deletion in the patient with inhibitor, partial gene deletion in another one, and missense mutations in 9 families. Mutation was not found in one patient. Actually, according to the data already published, only two patients were at high risk for inhibitor development in our population. Our study, although rather small, confirms the previously reported low incidence of inhibitors in haemophilia B. Large studies on incidence of FIX inhibitors are indeed difficult to perform, due to both the overall small number of severe haemophilia B patients and the low incidence of FIX inhibitors. Consequently, the impact of bias, such as prevalence of different types of gene defects in a given population, is major. Therefore, any study, dealing with incidence of FIX inhibitors in severe haemophilia B should report, for each patient, the type of gene defect.
Intracranial haemorrhage (ICH) is known to be a severe although uncommon complication of haemophilia. A national survey has been conducted in France in order to collect information about ICHs which ...occurred in haemophiliacs between 1991 and 2001 and to propose recommendations for the diagnostic and treatment of ICH. Within this period, 123 episodes of ICH were recorded from 106 patients. Two‐thirds of ICH concerned patients with severe haemophilia. Half of the cases occurred in patients under 15 years of age, 67.2% of which were post‐traumatic. Ten cases occurred in neonates with three fatal outcomes. Overall mortality was high (21.9%) suggesting that availability of clotting factor concentrates has not improved the prognosis of this event. Morbidity was also high with 60% of long‐term sequelae. The following parameters have been identified as prognostic factors for death: thrombocytopenia, HCV infection, intraventricular or intraparenchymatous haemorrhage. A delay in diagnosis was mentioned in 43.3% of cases, often related to the lack of recognition of the initial symptoms, which may be very common (apathy, tearfulness in young children and headache in elder patients). Delayed replacement therapy was recorded in 37.2% of cases. Emergency units initially dealt with half of these patients. Information concerning recognition and management of these episodes, not only in severe haemophilia, but also in moderate and mild forms, should be regularly supplied to paediatricians in maternity and physicians from emergency units, as well as to patients and their relatives.
Factor XI (FXI) deficiency is an inherited autosomal recessive disorder associated with bleeding of variable severity. However, many cases of dominant disease transmission have been recently ...described. This disorder is rare in the general population, whereas it is commonly found in individuals of Ashkenazi Jewish ancestry. This study reports the molecular genetic analysis of FXI deficiencies in 11 unrelated families of different origin. Five novel mutations have been identified. Severe FXI deficiency of two unrelated patients resulted from two novel mutations: one deletion (960-961delGT) in exon 9 predicting a frameshift, and a Ser-4Leu mutation located in the signal peptide. In addition, three novel missense mutations associated with partial FXI deficiency have been identified: Cys122Tyr, Glu297Lys and Glu579Lys.
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