Factor Vii Deficiency

The rare inherited disorders of coagulation are a fascinating group of diseases that have provided us with important insights into the structure and function of their respective deficient protein(s). Factor VII (FVII) deficiency is the commonest of the ‘rare inherited disorders of coagulation’ and this review summarizes current knowledge on the prevalence, diagnosis, management and the molecular pathology of factor VII deficiency. Vascular injury results in the binding of FVII to Tissue Factor (TF), a sequence of events that initiates coagulation and ultimately generates a massive but highly focused burst of thrombin at the site of vascular damage. FVII bound to TF is activated to generate the active serine protease FVIIa and it is the TF–VIIa complex that, through limited proteolytic cleavage, activates factors X and IX (Wildgoose et al, 1992a). The activated Factors Xa, VIIa, thrombin (IIa), IXa and XIIa have all been shown to activate FVII, but factor IXa in association with phospholipids appears to be most efficient at activating factor VII (Wildgoose Butenas exons 4 (residues 46–83) and 5 (residues 84–130) encode the two epidermal-like growth factor (EGF) domains, exons 6 (residues 131–167) and 7 (residues 168–208) encode the activation domain, and exon 8 (residues 209–406) encodes the catalytic domain and 1026 nucleotides of the 3′ non-coding sequence including the poly(A) tail. The F7 gene contains a number of polymorphisms, five (and possibly six) of which have also been shown to influence FVII activity (Table I). Other polymorphisms within the F7 gene have been reported but appear to be silent in terms of their effect upon protein function and/or secretion. In contrast to many eukaryotic promoters and both factor X and factor IX, the FVII promoter lacks both a TATA and CAAT box. The major transcription initiation site for FVII is located 50 bp upstream from the initiation codon– Methionine +1. Analysis of the FVII promoter shows that maximal FVII activity resides within a 185-bp fragment and DNAse I footprint analysis has identified protein binding sites at −51 to −32, −63 to −58, −108 to −84 and −233 to −215 (Pollak et al, 1996). In addition, binding sites for both HNF-4 and Sp1 have been demonstrated and disruption of either of these sites results in a loss of promoter activity (Pollak et al, 1996) and has been reported as a cause of factor VII deficiency (Arbini et al, 1997; Carew et al, 2000). Factor VII plasma levels are determined by both environmental and genetic factors with the latter accounting for up to one-third of the variation in plasma FVII levels (Bernardi et al, 1996). Among environmental factors, dietary fat intake and the levels of plasma triglycerides are positively correlated with factor VII:C levels, but other factors such as age, obesity, diabetes (Heywood et al, 1996) and, in women, the use of sex hormones can all affect FVII levels (Meade, 1988; Habiba et al, 1996). Five and possibly six polymorphisms within the human F7 gene have been shown to affect both plasma FVII:C levels and, more recently, plasma VIIa levels (Bernardi et al, 1997). The first polymorphism to be reported within the F7 gene that affects factor VII levels was the Arg353Gln polymorphism within exon 7, which arises from a G→A substitution at position 10976 (Green et al, 1991). This substitution has a frequency in the UK population of approximately 0·2 and heterozygosity for this polymorphism is associated with an approximately 25% reduction in factor VII coagulant (or functional) activity (FVII:C) and factor VII antigen (FVII:Ag) levels. Individuals homozygous for this polymorphism have an approximately 50% reduction in circulating plasma factor VII. The Arg353Gln polymorphism is commonly found in association with a second polymorphism – the insertion of a 10-bp sequence (decanucleotide) within the 5′ untranslated region of the factor VII gene at position −323 (Marchetti et al, 1992). Until recently it was unclear which of these two polymorphisms was responsible for the alteration in plasma factor VII levels. However, studies of a group of Polish blood donors in which the Arg353Gln polymorphism is not in strong allelic association with the 10 bp promoter insertion has shown that both the Arg353Gln polymorphism and the 10 bp promoter polymorphism independently affect circulating factor VII plasma levels (Hunault et al, 1997). Two additional polymorphisms within the FVII promoter at positions −401 (G→T) and −402 (G→A) have also been shown to affect factor VII levels (Marchetti et al, 1993; van't Hooft et al, 1999). A third polymorphism is located within intron 7 (IVS7) of the factor VII gene and is characterized by the presence of a variable number of a 37-base pair repeat sequence (Marchetti et al, 1991, 1992). In the first repeat, which also contains the IVS7 donor splice site, sequence variations have also been identified. Quantitative mRNA analysis has shown that the higher numbers of repeats are associated with relatively higher mRNA expression and suggests that the IVS7 polymorphism contributes to plasma FVII levels (Pinotti et al, 2000). Finally, a recently identified G to A polymorphism within intron 1a of the FVII gene at position +74 has also been shown to affect FVII levels (Peyvandi et al, 2000a), although it appears to be in strong linkage disequilibrium with both the 10-bp decanucleotide insertion and the Arg353Gln alleles. The diagnosis of factor VII deficiency is usually suspected following the identification of a prolonged prothrombin time which corrects, unless an inhibitor is present, in a 50:50 mix with normal plasma. The activated partial thromboplastin time (APTT), thrombin time and fibrinogen concentration are usually normal. Specific assays of factor VII are undertaken to confirm the deficiency. It is important to exclude vitamin K deficiency or other acquired causes of a clotting disorder before the diagnosis of factor VII deficiency is made. Family studies may also be of value in establishing the diagnosis of factor VII deficiency. Functional factor VII activity (FVII:C) is frequently measured using a one-stage prothrombin time (PT)-based assay et al, 1991). 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