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Coagulation factor VII, hemostasis and thrombosis
min-fused rFVIIa molecule showed enhanced transcellular transport upon intranasal delivery and extended plasma half-life in transgenic mice.78
The development of non-substitutive therapy for the hemophilias, such as the use of anti-antithrombin RNA interference or of aptamer and monoclonal antibodies directed against TFPI, have raised expectations for improvement of the quality of life in individuals with FVII deficiency.75
Based on adeno-associated viral-mediated expression of FVII79, gene therapy has produced sustained correction of severe FVII deficiency in dogs. In addition, gene therapy using FVIIa, inserted into the same viral vector, could also be used to treat congenital FVII deficiency with lower vec- tor doses, which increases the chance of efficient and long term expression of the transgene. Small engineered RNA have also been used as an approach of personalized gene therapy to correct a human FVII splicing mutation in mice.59
Factor VII levels, F7 genotypes and cardiovascu- lar disease
Several findings have created interest and still lead to an intense investigation on the role of FVII in cardiovascular disease (Figure 1B). Exposure of TF to blood in (coronary) artery disease, and especially plaque rupture, may favor FVIIa-TF complex formation. Further, lipids are important components of atherosclerosis and determinants of FVII activation and activity as well.79,80 Additional links between high FVII levels and risk for thrombosis have been suggested81 by finding that the TF-FVIIa-Xa complex activates FVIII before coagulation amplification and that heparanase increases generation of FXa by the FVIIa-TF- complex.82 Furthermore, the FVIIa-TF complex is believed to mediate non-hemostatic functions in diverse biological processes, such as angiogenesis, inflammation, atheroscle- rosis and vascular and cardiac remodeling, by activating signaling pathways (reviewed in D'Alessandro et al.)84 through FVIIa-integrin binding and PAR2 cleavage.85
The F7 promoter may respond to a number of metabolic components, and FVIIc levels are associated with several environmental factors linked to atherosclerosis i.e., body mass index, dietary fat intake, plasma lipids and particu- larly triglyceride concentration.
Age- and sex-related variations in FVII levels add com- plexity to the investigation of clinical correlates. FVII lev- els were found to increase with age and to be significantly lower in women than men at younger ages. Postmenopausal women displayed the highest levels, except when undergoing hormone replacement therapy.86 This conundrum of environmental factors interacts with the F7 gene variation.
Factor VII levels and F7/genome wide genotypes
FVII levels show ample variation in the normal popula- tion and have a substantial heritable component, also in relation to polymorphisms15 (Figure 4). Missense,87 repeat number variation,58 insertion/deletion22 and SNP23 were found to be associated with FVIIc, FVIIa and FVIIag levels (Figure 4) through epigenetic, transcription, biosynthesis- or stability-mediated mechanisms. Whereas twin studies88 estimated about 60% of genetic-associated level of vari- ance in plasma, the F7 locus variation accounted for up to
40% of variance. Genotype effects, perhaps stronger on FVIIa than on FVIIag (Figure 4),15 might modulate the response to environmental stimuli and the sex-dependent regulation.89 Serum phospholipids were found to be strong and F7 genotype-associated FVIIa determinants.90
The number of F7 single SNP was substantially increased by highthroughput F7 gene sequencing, which enabled very informative F7 population studies.91 Genome-wide association studies (GWAS) confirmed14,92 the strong association between FVII levels and F7 gene variation.93 Importantly, GWAS have detected a number of genomic regions associated with FVII levels (GCKR, ADH4, MS4A6A, PROCR, APOA5, HNF4A, REEP3- JMJD1C, JAZF1-AS1, MLXIPL and XXYLT1),14,92 that could explain an additional one fifth of the FVII variance in plas- ma levels and are also, in part, associated with lipids which in turn modulate FVII activity. These gene-based association scan initiatives have been established in sever- al populations.94 Overall, this picture defines one of the most extensively investigated relationship between geno- types and multiple quantitative phenotypes (FVIIc, FVIIag and FVIIa) (Table 1).
Levels, genotypes and cardiovascular disease
The Northwick Park Heart Study investigators were the first to report that high FVII levels were predictors of death due to coronary disease,16 and a number of studies confirmed this observation in different populations by also evaluating FVIIa levels.95
Recent investigations on the level of the FVIIa-AT com- plex, which may reflect levels of FVIIa as well its interac- tion with TF, indicated that higher complex concentra- tions were associated with increased mortality in the Cardiovascular Health Study.96 In patients with stable coronary artery disease (Verona Heart Study) higher FVIIa- AT complex levels were associated with increased cardio- vascular mortality and increased thrombin and FXa gener- ation,97 particularly in the coagulation initiation phase.98 However, in small groups of patients with unstable angi- na, acute myocardial infarction99 or post-infarction80 FVIIa levels were not higher than in controls. High plasma FVIIag levels were associated with failure of thrombolytic therapy in patients with myocardial infarction.100 Elevated levels of FVII have not been consistently associated with venous thromboembolism.101
The influence of F7 genotypes on the hemostatic bal- ance and on the susceptibility to cardiovascular disease has been extensively investigated in several large cohorts of patients in relation to both myocardial infarction and stroke. F7 polymorphisms with an opposite effect on FVIIa levels may positively or negatively modulate the risk of MI in males with advanced coronary artery disease,18 and some FVII genotypes may protect against myocardial infarction17 by affecting transcription levels and reducing protein functional activity. The modulation of stroke risk in atrial fibrillation by F7 genotypes may follow a similar scheme102 and recently, in a meta-analysis of several GWAS14 variations in FVII-related genes and FVIIc levels were associated with a risk of the incidence of ischemic stroke in the general population. The physiological effects of FVII lowering alleles may represent a natural model for anticoagulation; in fact F7 polymorphisms were shown to play a role in determining the initial response to war- farin103 and influencing the risk of thrombosis in patients with essential thrombocythemia104.
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