Major differences in bleeding symptoms between factor VII deficiency and hemophilia B
ABSTRACT 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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ABSTRACT: The eighth edition of the haemophilia B database (http://www.umds.ac. uk/molgen/haemBdatabase.htm ) lists in an easily accessible form all known factor IX mutations due to small changes (base substitutions and short additions and/or deletions of <30 bp) identified in haemophilia B patients. The 1713 patient entries are ordered by the nucleotide number of their mutation. Where known, details are given on: factor IX activity, factor IX antigen in circulation, presence of inhibitor and origin of mutation. References to published mutations are given and the laboratories generating the data are indicated.Nucleic Acids Research 01/1998; · 8.28 Impact Factor
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ABSTRACT: The World Federation of Hemophilia estimates that of the 400,000 individuals worldwide with hemophilia, 300,000 receive either no, or very sporadic, treatment. Thus, considerable innovation will be required to provide cost-effective therapies/cures for all affected individuals. The high cost of prophylactic regimens hampers their widespread use, which further justifies the search for novel cost-effective therapies and ultimately a cure. Five gene transfer phase I clinical trials have been conducted using either direct in vivo gene delivery with viral vectors or ex vivo plasmid transfections and reimplantation of gene-engineered cells. Although there was evidence of gene transfer and therapeutic effects in some of these trials, stable expression of therapeutic factor VIII or FIX levels has not yet been obtained. Further improvements of the vectors and a better understanding of the immune consequences of gene transfer is warranted, as new trials are being initiated. Bioengineered clotting factors with increased stability and/or activity are being validated further in preclinical studies. Novel clotting factor formulations based on PEGylated liposomes with prolonged activities are being tested in the clinic, and are yielding encouraging results.Journal of Thrombosis and Haemostasis 06/2007; 5(5):901-6. · 6.08 Impact Factor
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ABSTRACT: Two different human genomic DNA libraries were screened for the gene for blood coagulation factor IX by employing a cDNA for the human protein as a hybridization probe. Five overlapping lambda phages were identified that contained the gene for factor IX. The complete DNA sequence of about 38 kilobases for the gene and the adjacent 5' and 3' flanking regions was established by the dideoxy chain termination and chemical degradation methods. The gene contained about 33.5 kilobases of DNA, including seven introns and eight exons within the coding and 3' noncoding regions of the gene. The eight exons code for a prepro leader sequence and 415 amino acids that make up the mature protein circulating in plasma. The intervening sequences range in size from 188 to 9473 nucleotides and contain four Alu repetitive sequences, including one in intron A and three in intron F. A fifth Alu repetitive sequence was found immediately flanking the 3' end of the gene. A 50 base pair insert in intron A was found in a clone from one of the genomic libraries but was absent in clones from the other library. Intron A as well as the 3' noncoding region of the gene also contained alternating purine-pyrimidine sequences that provide potential left-handed helical DNA or Z-DNA structures for the gene. KpnI repetitive sequences were identified in intron D and the region flanking the 5' end of the gene. The 5' flanking region also contained a 1.9-kb HindIII subfamily repeat. The seven introns in the gene for factor IX were located in essentially the same position as the seven introns in the gene for human protein C, while the first three were found in positions identical with those in the gene for human prothrombin.Biochemistry 08/1985; 24(14):3736-50. · 3.38 Impact Factor