Major differences in bleeding symptoms between Factor VII deficiency and Haemophilia B

Journal of Thrombosis and Haemostasis (Impact Factor: 5.72). 04/2009; 7(5):774 - 779. DOI: 10.1111/j.1538-7836.2009.03329.x


Background: The autosomally-inherited factor VII (FVII) deficiency and X-linked hemophilia B offer an attractive model to investigate whether reduced levels of FVII and FIX, acting in the initiation and amplification of coagulation respectively, influence hemostasis to a different extent in relation to age and bleeding site. Methods: Hemophilia B patients (n = 296) and FVII-deficient males (n = 109) were compared for FVII/FIX clotting activity, F7/F9 genotypes and clinical phenotypes in a retrospective, multi-centre, cohort study. Results: Major clinical differences between diseases were observed. Bleeding occurred earlier in hemophilia B (median age 2.0 years, IR 0.9–5.0) than in FVII deficiency (5.2 years, IR 1.9–15.5) and the bleeding-free survival in FVII deficiency was similar to that observed in ‘mild’ hemophilia B (P = 0.96). The most frequent disease-presenting symptoms in hemophilia B (hematomas and oral bleeding) differed from those in FVII deficiency (epistaxis and central nervous system bleeding). Differences were confirmed by analysis of FVII-deficient women. Conclusions: Our data support the notion that low FVII levels sustain hemostasis better than similarly reduced FIX levels. On the other hand, minute amounts of FVII, differently to FIX, are needed to prevent fatal bleeding, as indicated by the rarity of null mutations and the associated life-threatening symptoms in FVII deficiency, which contributes towards shaping clinical differences between diseases in the lowest factor level range. Differences between diseases are only partially explained by mutational patterns and could pertain to the specific roles of FVII and FIX in coagulation phases and to vascular bed-specific components.

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Available from: Mario Lapecorella, Dec 09, 2014
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    • ".org/)[1] [2] [3] of F9 gene [4] displays a large predominance of missense mutations (>65%), mainly occurring in the chymotrypsin-like catalytic domain. Notwithstanding, only few pathogenic molecular mechanisms have been detailed [5] [6] [7] [8]. "
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    ABSTRACT: The interplay between impaired protein biosynthesis and/or function caused by missense mutations, particularly in relation to specific protein regions, has been poorly investigated. As model we chose the severe p.Y450C mutation in the carboxyl-terminal region of coagulation factor IX (FIX) and, by expression of a panel of recombinant variants, demonstrated the key role of the tyrosine phenyl group for both FIX secretion and coagulant activity. Comparison among highly homologous coagulation serine proteases indicate that additive or compensatory pleiotropic effects on secretion and function by carboxyl-terminal mutations produce life-threatening or mild phenotypes in the presence of similarly reduced protein amounts.
    Full-text · Article · Aug 2013 · FEBS letters
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    • "FIX coagulant activity was assessed by the aPTT coagulation assay (48). FIX antigen levels in the conditioned medium were evaluated by ELISA (Factor IX antigen, FIX; Affinity Biologicals, Ancaster, Canada). "
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    ABSTRACT: A significant proportion of disease-causing mutations affect precursor-mRNA splicing, inducing skipping of the exon from the mature transcript. Using F9 exon 5, CFTR exon 12 and SMN2 exon 7 models, we characterized natural mutations associated to exon skipping in Haemophilia B, cystic fibrosis and spinal muscular atrophy (SMA), respectively, and the therapeutic splicing rescue by using U1 small nuclear RNA (snRNA). In minigene expression systems, loading of U1 snRNA by complementarity to the normal or mutated donor splice sites (5′ss) corrected the exon skipping caused by mutations at the polypyrimidine tract of the acceptor splice site, at the consensus 5′ss or at exonic regulatory elements. To improve specificity and reduce potential off-target effects, we developed U1 snRNA variants targeting non-conserved intronic sequences downstream of the 5′ss. For each gene system, we identified an exon-specific U1 snRNA (ExSpeU1) able to rescue splicing impaired by the different types of mutations. Through splicing-competent cDNA constructs, we demonstrated that the ExSpeU1-mediated splicing correction of several F9 mutations results in complete restoration of secreted functional factor IX levels. Furthermore, two ExSpeU1s for SMA improved SMN exon 7 splicing in the chromosomal context of normal cells. We propose ExSpeU1s as a novel therapeutic strategy to correct, in several human disorders, different types of splicing mutations associated with defective exon definition.
    Full-text · Article · Feb 2012 · Human Molecular Genetics
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    • "The only difference is the presence of only females in the lowest FVII:C level group. At any rate, in previous studies (Mariani et al 2003, 2005, Bernardi et al, 2009 "
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    ABSTRACT: 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.
    Full-text · Article · Feb 2011 · British Journal of Haematology
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