Angelika Batorova

Factor VII deficiency: clinical manifestation of 717 subjects from Europe and Latin America with mutations in the factor 7 gene

Summary.  Inherited factor X deficiency (FXD) is a rare (1:1 000 000) recessive bleeding disorder. The clinical and laboratory phenotypes of FXD are poorly correlated and few regional studies on the genotype and the clinical manifestations of FXD are known. To understand the association between clinical manifestations and causative genotype, detailed evaluation of bleeding pattern in a high number of patients is needed. This international study analysed the phenotype and genotype of 102 subjects from Central Europe (Germany, Poland and Slovakia) and Latin America (Costa Rica and Venezuela) with causative mutations in the F10 gene, via sequencing. Twenty‐eight homozygous, seven compound‐heterozygous and 67 heterozygous FXD subjects were characterized. Twenty‐nine different causative mutations, including 15 novel mutations, were analysed. Spontaneous bleeding symptoms in 42 symptomatic individuals (26 homozygous, seven compound heterozygous and nine heterozygous) comprised easy bruising (55%), haematoma (43%), epistaxis (36%), haemarthrosis (33%), intracranial haemorrhage (ICH; 21%), and gastrointestinal (GI) haemorrhage (12%). The manifestation of bleeding symptoms in 9 of 67 (13%) symptomatic heterozygous subjects is described. The bleeding patterns of the enrolled patients showed differences that are associated with the types of F10 mutation, and the corresponding genotypes. The homozygous patients were evaluated for genotype–phenotype correlation. The results suggested that ICH seems to be associated with the F10 mutation Gly380Arg, and possibly with the mutations IVS7–1G > A and Tyr163delAT. A tentative association of other mutations to severe symptoms such as haemarthrosis and GI haemorrhage is reported. The severity of FXD, the genotype–phenotype association, and the results of regional studies are discussed.

Thrombosis in inherited factor VII deficiency.

Summary.  Thrombosis in congenital factor (F) VII deficiency was investigated through extensive phenotypic and molecular‐genetic studies. Patients with a history of thrombosis among 514 entries in the FVII Deficiency Study Group database were evaluated. Thrombotic events were arterial in one case, disseminated intravascular coagulation in another and venous in seven. Gene mutations were characterized in eight patients: three were homozygous, three compound heterozygous and two heterozygous. FXa and IIa generation assays were consistent with the genetic lesions. One patient was heterozygous for the FV Leiden and one for the FIIG20210A mutation. In seven patients, surgical interventions and/or replacement therapies had a close temporal relationship with thrombosis, while in the remaining, events were apparently spontaneous. Thromboses were not associated with any specific age, phenotype, mutation zygosity or thrombophilic abnormalities. In particular, severe FVII deficiency did not seem to offer protection from strong thrombosis risk factors such as surgery and replacement therapy.

Intermittent injections vs. continuous infusion of Factor VIII in haemophilia patients undergoing major surgery

Continuous infusion (CI) of factor VIII (FVIII) has been proved to be a safe alternative to intermittent bolus injections (BI) in haemophilia A. Most reports on CI suggest a considerable saving in FVIII compared with historical controls treated with BI, but some recent reports failed to demonstrate such an effect. The present study prospectively compared safety, efficacy and factor requirements in 43 major surgical procedures performed in severe haemophilia A patients who were treated with either BI (18 operations) or CI (25 operations). The aim was to maintain factor VIII levels above the same minimum levels. Improved safety of CI over BI was observed, despite a bias in favour of the BI group (all underwent unilateral operations, compared with 24% of the CI group who underwent bilateral operations). Higher nadir levels were found in the CI group (0·44 ± 0·06 vs. 0·31 ± 0·09 IU/ml; P < 0·01) with a lower incidence of dangerous drops below 0·3 IU/ml (8% vs. 44% of patients respectively; P < 0·01), and a lower drop in haemoglobin (Hb) (1·56 ± 1·21 vs. 3·01 ± 2·13 g/dl; P < 0·05) and blood transfusion requirements (12% vs. 39%; P < 0·01). Major bleeding complications developed in three out of 18 patients (17%) in the BI group and none of the CI group (P = 0·06). The FVIII dosage was lower by 36% in the CI group (467 ± 104 vs. 733 ± 126 IU/kg; P < 0·01). Had the trough factor levels been maintained at the target levels, a greater difference of 72% would probably have been observed.

Continuous infusion of coagulation factors

Summary.  Continuous infusion (CI) of coagulation factor concentrate is aimed at maintaining a steady haemostatic level of the missing factor in circulation, preventing dangerous troughs below the haemostatic level and unnecessary high peaks, which increase the safety and decrease the consumption of factor concentrate replacement therapy. This can be achieved by the administration of the coagulation factor at a rate corresponding to its elimination. CI has been used in wider extent since the early 1990s, after the resolution of basic questions such as the stability of factor concentrates after reconstitution, the risk of contamination and bacterial overgrowth in these biological materials during either preparation of infusion bags or prolonged administration, the frequent local thrombophlebitis, the knowledge of pharmacokinetics of coagulation factors in the conditions of CI and the developement of adequate minipumps. The increasing clinical experience with CI used in haemophilia A and B and von Willebrand disease has proven the advantages of this mode of replacement therapy, providing improved margins of efficacy and safety in various clinical settings requiring the maintenance of haemostatic levels over prolonged periods, as well as reduction in treatment cost compared with the traditional therapy via intermittent injections of coagulation factors.Keywords: continuous infusion, factor VIII, factor IX, haemophilia, recombinant FVIIIa, von willebrand disease.

Recombinant, activated factor VII for surgery in factor VII deficiency: a prospective evaluation – the surgical STER

Excessive bleeding represents a major complication of surgical interventions and its control is especially relevant in patients with Congenital Bleeding Disorders (CBD). In factor VII (FVII) deficiency, scanty data on surgery is available to guide treatment strategies. The STER (Seven Treatment Evaluation Registry) is a multi‐centre, prospective, observational, web‐based study protocol providing the frame for a structured and detailed data collection. Inhibitor occurrence was checked in a centralized fashion. Forty‐one surgical operations (24 ‘major’ and 17 ‘minor’) were performed in 34 subjects with a carefully characterized FVII deficiency under the coverage of recombinant activated Factor VII (rFVIIa). Bleeding occurred during three major interventions of orthopaedic surgery, but rFVIIa was given at very low dose in each case. An antibody to FVII was observed in one patient who underwent a multiple dental extraction. No thromboses were reported during the 30‐d follow up period. Replacement therapy with rFVIIa proved effective when suitable doses were used, which, during the period of maximum bleeding risk (the day of operation), were calculated (Receiver Operated Characteristic analysis) to be of at least 13 μg/kg/body weight per single dose and no less than three administrations. This indication is important especially in the case of major surgery.

Continuous infusion of coagulation factors : current opinion

Purpose of reviewTo review the most recent reports on continuous infusion of coagulation factors, focusing on the current issues relating to this mode of therapy. Recent findingsContinuous infusion has been extensively used as an alternative to intermittent bolus factor replacement since the 1990s. To date, more than 100 reports comprising more than 800 continuous infusion treatments in various clinical situations have been published, with an increase in the current utilization of recombinant coagulation factors. An excellent hemostatic efficacy of continuous infusion has been reported. Continuous infusion protocols, however, still vary widely in terms of the different hemostatic levels targeted, dosage regimens, modes of continuous infusion and duration of therapy, which obviously result in variations in the cost-effectiveness reported by different centers. SummaryContinuous infusion has been shown to be a safe and cost-effective mode of replacement for treatment of hemophilia. The lack of evidence-based information on the hemostatic levels to be maintained in specific clinical situations, and recent concerns regarding the development of inhibitors, particularly in patients with mild hemophilia treated with continuous infusion, need to be addressed by prospective, randomized studies that compare traditional intermittent injections and the continuous infusion mode of factor replacement.

Continuous infusion in haemophilia: current practice in Europe

Summary. Continuous infusion (CI) of factor VIII (FVIII) is an effective method for replacement therapy in haemophilia. Recently, concerns have been raised regarding association of CI with the development of inhibitors. The aim of this study was to gain information on the current practices in Europe regarding CI and the true inhibitor incidence after this mode of therapy. In a cross sectional study performed in 22 Comprehensive Care Centres (CCCs), we evaluated CI techniques, treatment protocols, efficacy, safety and complications of CI including inhibitors. Thirteen (59%) CCCs reported a total of 1079 CI treatments, given peri‐operatively or for major bleeds, in 742 patients. Most centres used ‘adjusted dose’ CI aimed at median target FVIII level of 0.8 IU mL‐1. CI was haemostatically very effective with a low incidence of complications: median incidence of postoperative bleeding was 1.8%, six centres observed phlebitis in 2–11% of CI treatments. Only nine (1.2%) patients developed inhibitors (0.45% of 659 severe and 7.2% of 83 mild haemophilia patients). Additional analysis of inhibitor patients revealed several confounding factors (low number of prior FVIII exposure days, high steady‐state factor levels during CI, high‐risk genotype). In this unprecedentedly large cohort, CI treatment appears to be an effective and safe treatment that does not increase the risk of inhibitor development in patients with severe haemophilia. Thus, previous small case series reports suggesting that CI may increase inhibitorsb cannot be confirmed. Inhibitor risk in mild haemophilia could not be evaluated as the influence of other, potentially confounding, risk factors could not be excluded.

Inhibitors to factor VII in congenital factor VII deficiency

FVIII inhibitors are more likely to have uncommon FVIII haplotypes not seen in caucasians. Our patient was hemizygous for FVIII haplotype H2 and his donor was heterozygous for H1 and H2. We speculate that ‘mismatch’ of FVIII haplotypes between donor and recipient might have contributed to inhibitor development, but we cannot prove this in a chimeric immune system that was in part from a donor heterozygous for FVIII H1 and H2 haplotypes. Regardless of the mechanism by which the inhibitor arose in our patient, this case serves as a useful example of successful management of bleeding with OBI-1 and subsequent elimination of the inhibitor without disrupting his stem cell transplant. Acknowledgements

Evaluation of factor V mRNA to define the residual factor V expression levels in severe factor V deficiency.

We evaluated FV mRNA in severe factor V deficiency caused by the -12T/A IVS18 mutation, activating a cryptic splice site and leading to premature translation termination. Quantitative evaluation of factor V cDNA from homozygous and heterozygous subjects, and correction for nonsense mediated decay, suggested the presence of 0.1% of normal factor V mRNA.

Pharmacokinetic properties of recombinant FVIIa in inherited FVII deficiency account for a large volume of distribution at steady state and a prolonged pharmacodynamic effect

Pharmacokinetic properties of recombinant FVIIa in inherited FVII deficiency account for a large volume of distribution at steady state and a prolonged pharmacodynamic effect -