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Coagulation factor VII, hemostasis and thrombosis
FVII deficiency is believed to be very rare (one case in 500,000 individuals).36,37 The World Federation of Hemophilia38 estimates around 5,000 FVII-deficient indi- viduals in the countries covered by this organization. However, the Italian Registry of Congenital Rare Bleeding Disorders39 (RBD) reported 1,023 cases with FVII deficien- cy among the 2,178 patients registered. This figure, similar to that reported by the UK registry (n=1.373),38 suggests a prevalence only slightly lower than that of hemophilia B, at least in Italy (FVII deficiency, 1:59,000; haemophilia B, 1:67,000 individuals). Accordingly, FVII deficiency accounts for the most frequent RBD in most registries (36- 49%).37,39 These data support the concept (Table 1) that FVII deficiency, including mild, moderate and severe forms, might be much more prevalent than previously reported. Large differences in prevalence, with variation reaching one order of magnitude, have been reported in those geographical areas where consanguineous marriages are frequent.
Clinical picture
The bleeding tendency in FVII deficiency varies from forms more severe than those seen in the hemophilias40 to very mild forms or asymptomatic cases. A simple classifi- cation of the clinical severity was proposed:10 i) severe forms (central nervous system [CNS] and/or gastrointesti- nal [GI] bleeding and/or hemarthrosis; ii) moderate forms
(three or more symptoms other than CNS and/or GI bleeding and/or hemarthrosis); iii) mild forms (one or two symptoms, mostly muco-cutaneous, and other than CNS and/or GI and/or hemarthrosis).
In the International F7 Registry and the Seven Treatment Evaluation Registry (STER)41 that include 787 cases, 12% of individuals had a severe to very severe phe- notype and three fourth of them bled within the first year of age (Table 4). About 20% of individuals with FVII defi- ciency suffer from a bleeding disorder that can be life- threatening and/or be a major handicap. On the other hand, the most frequently observed patient cohort (>50%) is characterized by muco-cutaneous types of bleeding: epistaxis (two thirds), gum bleeding (one third), easy bruising (one third), and menorrhagia (70% of the females). In general, the bleeding tendency remains the same during the lifetime of the patient with the first bleeding event being a strong and independent predictor of the risk for the subsequent bleeding phenotype.41 Co- inheritance of factor V Leiden enhances thrombin forma- tion and is associated with a mild bleeding phenotype.42
Levels of FVIIc higher than 26%11,41,43 may have a nil or minimal clinical relevance in terms of spontaneous bleed- ing and subjects with FVIIc levels <10% who remain asymptomatic most of their lives are not rare in being diagnosed during family studies or hemostatic screenings.10,11,35
Table 1. Distinctive features of coagulation factor VII (FVII), activated FVII , FVII deficiency, FVII levels and cardiovascular disease.
FVII
Very low plasma concentrations (0.5 mg/mL)
Short half-life 2-4 hours Stable in plasma
Conserved in all jawed vertebrates
High similarity with factor IX, factor X and Protein C
FVII (FVIIa)
First protease in the coagulation cascade.
Lowest catalytic activity without cofactor (TF).
Half-life of FVIIa
and FVII similar (2-3 hours) rFVIIa for replacement therapy
F7 polymorphisms are strong predictors of FVIIa levels
Very low amounts of FVIIa sufficient to initiate coagulation
«Stable» FVIIa-AT complex
FVII deficiency
Highest prevalence among autosomally recessive rare bleeding disorders
Complete deficiency results in perinatal mortality
High incidence of intracranial
bleeding (severe form)
Wide variation of bleeding phenotype
in relation to modest FVII level variations
Homozygous FVII-lowering alleles mimic Mendelian heterozygous deficiency
FVII levels
High variability in human populations High number of environmental determinants
High proportion of variance explained by F7 gene variation
The genotype/phenotype relationship is one of the most extensively investigated among human genes
Frequent FVII level- lowering alleles with wide differences in human populations
High/low levels associated with predisposition/ protection towards/from cardiovascular disease
FVII: factor VII; FVIIa: activated FVII; rFVIIa: recombinant FVIIa; TF: tissue factor; AT: serpin antithrombin; F7: factor VII gene.
Table 2. Some open issues in factor VII (FVII) protein and F7 genetics, FVII deficiency, FVII levels and cardiovascular disease.
FVII / F7 Mechanisms underlying
FVIIa levels
Decryption of TF for FVIIa binding and catalytic activity
Physiological balance between
F7 gene variation cardiovascular disease
Population features causing large differences in the prediction of cardiovascular disease risk by F7 genotypes
Impact of FVII-lowering alleles in the protection from cardiovascular disease
Impact of FVII-increasing alleles in the predisposition
toward specific cardiovascular disease forms
FVII deficiency
Residual FVII concentration predicting the most severe symptoms is still puzzling.
Residual FVII concentration preventing spontaneous bleeding is difficult to define.
Short plasma half life of FVII/rFVIIa for therapeutic purposes.
Discrepancy between rFVIIa pharmacokinetic and pharmacodynamic data
Impact of FVII-lowering alleles in increasing the
clinical penetrance of pathological F7 gene lesions FVII: factor VII; FVIIa: activated FVII; rFVIIa: recombinant FVIIa; TF: tissue factor; F7: factor VII gene.
FVIIa inhibitors
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