British Journal of Haematology, 2002, 118, 689700

Review
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.
THE ROLE OF FACTOR VII IN THE INITIATION
OF COAGULATION
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 TFVIIa 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 & Kisiel,
1989; Butenas & Mann, 1996).
Factor VII biochemistry
Factor VII is a vitamin K-dependent glycoprotein and
comprises 406 amino acids with a molecular weight of
50 kDa. FVII circulates in plasma in two forms the
majority as a single-chain inactive zymogen with a
concentration of 10 nmol/l (05 lg/ml) and a much smaller
amount (10110 pmol/l) as the active two-chain form
(Wildgoose et al, 1992a). The conversion of the single-chain
form of FVII to the two-chain form occurs by cleavage of a
single peptide bond between Arginine 152 and Isoleucine
153, resulting in a light chain of 20 kDa (residues 1152)
and a heavy chain of 30 kDa (residues 153406 see
Fig 1) and which contain the NH2- and COOH-terminal
ends of the parent molecule respectively.
FVII contains 10 glutamic acid residues located towards
the N-terminus of the molecule at residues 6, 7, 14, 16, 19,
20, 25, 26, 29 and 35. Post-translational modification of
these residues to c-carboxyglutamic acid (Gla) residues
allows the binding of calcium, which causes a conformaCorrespondence: David J. Perry MD PhD FRCP FRCPath, Senior
Lecturer/Honorary Consultant, Haemophilia Centre and Haemostasis Unit, Royal Free and University College Medical School, Royal
Free Campus, Pond Street, London NW3 1QG, UK. E-mail: d.perry@
rfc.ucl.ac.uk

2002 Blackwell Science Ltd

tional change in the molecule, exposing novel epitopes that

facilitate its subsequent binding to TF and phospholipid
(Wildgoose et al, 1992b).
FVII is a glycoprotein with O-linked glycosylation sites at
Serine 52 and 60 and N-linked sites at Asn145 and 322.
Glycosylation of FVII may be important for both its function
and for its plasma half-life. The triad of amino acids Serine
344, Aspartate 242 and Histidine 193, which constitute the
catalytic centre of FVIIa, are located on the heavy chain.
Regulation of FVIIa activity
The most important physiological inhibitor of the TFVIIa
complex is Tissue Factor Pathway Inhibitor (TFPI), a
member of the Kunitz family of inhibitors (van der Logt
et al, 1991). Human TFPI is a 276-amino-acid molecule
with a molecular weight of 32 kDa which circulates in
plasma associated with lipoproteins, at a low concentration
of 60180 ng/ml. TFPI is synthesized by megakaryocytes
and endothelial cells and its release from the surface of
endothelial cells is increased both by heparin and various
platelet agonists. TFPI forms an inactive quaternary complex comprising TFVIIa, factor Xa and TFPI which rapidly
inhibits the extrinsic pathway of coagulation. Antithrombin
in the presence of heparin may also be involved in the
regulation of FVIIa but its precise role remains controversial
(Jesty et al, 1996).
FACTOR VII GENE
The factor VII gene (F7) maps to the long arm of
chromosome 13 at 13q34, approximately 28 kb telomeric
to the factor X gene (Miao et al, 1992). The F7 gene spans
approximately 12kb of DNA and consists of nine exons
encoding a mature protein of 406 amino acids (Fig 1). FVII
is synthesized with either a 38-amino-acid or a 60-aminoacid prepro-leader sequence containing a hydrophobic
region (residues )36 to 24) which targets the protein for
secretion and a pro sequence (residues )17 to )1) which is
important for vitamin K-dependent gamma-carboxylation
and which is highly conserved among other vitamin
K-dependent proteins. The difference in the length of the
prepro-leader sequence arises from alternative splicing of
exon 1a/1b (Berkner et al, 1986). Exon 1b (66 bp of DNA
encoding amino acid residues )39 to )18) is absent in
approximately 90% of factor VII mRNA transcripts (Berkner
et al, 1986). The pro-peptide and the Gla domain are
encoded by exon 2. The pro-peptide is released from the
mature protein by cleavage between Arginine )1 and
Alanine +1. Exon 3 (residues 3845) encodes the hydrophobic aromatic stack; exons 4 (residues 4683) and 5

689

690

Review

Fig 1. Organization of the human factor VII gene and its encoded polypeptide. The upper part of the illustration represents the factor VII gene
with the 9 exons shown by filled boxes. The position of the first and last nucleotides of each exon are shown (numbered according to OHara
et al, 1987). The lower part of the illustration shows the polypeptide structure and the various functional domains encoded by specific exons.
Darker hatching indicates the prepro-peptide and lighter hatching the mature protein. Codons initiating each exon are shown (residue +1 is
the first amino acid of the mature protein). Activation of factor VII occurs through cleavage at Arg152Ile153 to generate a two-chain
molecule. The light chain is encoded by residues +1 to 152 and the heavy chain by residues 153 to 406. The heavy and light chains of FVIIa
are joined by a disulphide bond between Cys135 and Cys236. His193, Asp242 and Ser344 are the residues which constitute the catalytic
triad. ( ) shows the position of the 10 Gla residues and ( ) the position of O- and N-linked glycosylation sites.

(residues 84130) encode the two epidermal-like growth

factor (EGF) domains, exons 6 (residues 131167) and 7
(residues 168208) encode the activation domain, and
exon 8 (residues 209406) 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.

Table I. Factor VII gene polymorphisms.

Polymorphism type

Location

Alleles

Frequency

Decanucleotide [CCTATATCCT] insertion*

5 region ()323)

Arg353Gln polymorphism*

Exon 8

VNTR repeat (37 bp monomer repeat)*

Intron 7

Intron 1a (G74A)*

Intron 1a

Dimorphism (His 115)

Exon 5

G/A dimorphism (Ser 333)

Exon 8

G/T dimorphism*

5 region ()401)

G/A dimorphism*

5 region ()402)

G/A dimorphism

Intron 7

No insertion
Insertion
Arg353 (10976 C)
Gln353 (10976 T)
A (7)
B (6)
74 G
74 A
7880 C
7880 T
10916 G
10916 A
)401 G
)401 T
)402 G
)402 A
10523 G
10523 A

077
023
080
020
031
066
079
021
080
020
099
001
091
009
071
029
082
018

*Polymorphisms within the F7 gene that may influence circulating FVII levels.

2002 Blackwell Science Ltd, British Journal of Haematology 118: 689700

Review

691

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).

etti 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.

FACTOR VII LEVELS AND FACTOR VII GENE

POLYMORPHISMS

FACTOR VII ASSAYS

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 02 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;
vant 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 (March-

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 FVII assays
Functional factor VII activity (FVII:C) is frequently measured using a one-stage prothrombin time (PT)-based assay
(Poggio et al, 1991). However, the source of thromboplastin
used in the assay can have a significant effect upon the FVII
functional assays and for these reasons a series of different
thromboplastins are often used when investigating patients
with suspected factor VII deficiency (Poggio et al, 1991).
These potential problems are highlighted by Factor VII
Padua, a variant molecule characterized by a prolonged
rabbit brain prothrombin time, a normal Stypven cephalin
clotting time and a normal Thrombotest. Factor VII activity
is low when assayed using rabbit brain thromboplastin but
is normal when assayed using ox brain thromboplastin.
Factor VII antigen is normal and there is usually no
bleeding history (Girolami et al, 1978).
Because of limited conversion of FVII to FVIIa during
functional FVII assays, FVII:C measures both the inactive
zymogen, FVII and preformed FVIIa. FVII:C assays using
bovine thromboplastin are more sensitive to preformed
FVIIa (compared with zymogen FVII) than assays based on
human or rabbit thromboplastins. Between 8% and 30% of
the FVII:C activity of assays based on rabbit or bovine
thromboplastin is attributable to preformed FVIIa, while the
remaining 7092% is due to zymogen FVII (Morrissey,
1996).
Immunological FVII assays
FVII:Ag is frequently measured using an enzyme-linked
immunosorbent assay (ELISA) or immunoradiometric assay
(IRMA) and either monoclonal or polyclonal antibodies

2002 Blackwell Science Ltd, British Journal of Haematology 118: 689700

Review

(Boyer et al, 1986; Tirindelli et al, 1987; Coppola et al,

1992). Such assays can detect as little as 00001 l/ml of
factor VII (Coppola et al, 1992).

Number of cases
Deficiency*

Iran

Italy

UK

Fibrinogen
Prothrombin
Factor V
Factor V & VIII
Factor VII
Factor X
Factor XIII
Factor VIII
Factor IX
Factor XI

70
15
70
80
300
60
80
3000
900
20

10
7
21
29
58
16
31
3428
626
60

11
1
28
18
62
25
26
3554
762
150

*Only patients with factor levels of 10 l/dl or less

are included (for fibrinogen deficiencies 01 g/l or
less).
The populations of Iran, Italy and the UK are very
similar at 64 m, 578 m and 60 m respectively.

factor VII exhibiting very few symptoms while others with

much higher levels have a significant bleeding diathesis
(Triplett et al, 1985).
Spectrum of bleeding problems in patients with FVII deficiency
In patients with severe haemophilia A or B, the disease is
characterized by recurrent spontaneous bleeds into joints
and muscles with little in the way of mucosal-type bleeding.
In factor VII deficiency, the spectrum of bleeding problems is
very variable (Fig 2) (Peyvandi et al, 1997; Mariani et al,

100
Frequency of Bleeding
Symptoms(%)

80
60
40
20

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Inherited factor VII deficiency is the most common of the

rare inherited coagulation disorders, with an estimated
prevalence of between 1:300 000 and 1:500 000. Factor
VII deficiency is inherited in an autosomal recessive manner
and its frequency is significantly increased in countries
where consanguineous marriage is practised (Table II). For
reasons which are unclear, there is a relatively poor
correlation between factor VII levels and the risk of
bleeding, with some individuals having very low levels of

or

Ep

is

FACTOR VII DEFICIENCY

rh

ta

Factor VIIa assays

In samples in which there has been no activation of FVII,
assays for FVII:C and FVII:Ag should be equivalent. However, if there has been significant activation then these
results will clearly differ. The direct assay of FVIIa was
initially reported using a mutant Tissue Factor molecule in
which the transmembrane and cytoplasmic domains were
deleted (sTF1219), resulting in a soluble Tissue Factor
(sTF) which was selectively deficient in promoting the
conversion of FVII to FVIIa but which retained cofactor
activity toward factor VIIa in a one-stage clotting assay
(Neuenschwander & Morrissey, 1992; Morrissey et al,
1993). The basal FVIIa level in normal plasma measured
using this technique is approximately 36 ng/ml (Morrissey
et al, 1993), about 1% of the total circulating FVII mass.
A second method for the assay for FVIIa levels in plasma
has been reported that does not depend upon its functional
activity but involves a specific immunoassay using a unique
capture antibody with a high specificity for two-chain FVIIa
(Philippou et al, 1997). The activity-based assay for FVIIa
and the ELISA show excellent agreement when measuring
purified factor VII added to plasma (Philippou et al, 1997).
However, results from the two assays differ greatly when
used to measure the basal endogenous levels of FVIIa in
plasma. The ELISA estimates that normal plasma contains
approximately 00125 ng/ml ( 001 ng/ml) of FVIIa,
approximately 100-fold lower than that measured by the
activity sTF-based assay. The explanation for the discrepancy between the two assays is unclear although various
mechanisms have been proposed. It is possible that the
C-terminus of the light chain, towards which the capture
antibody in the ELISA is directed, may undergo proteolysis
in the circulation. This would render FVIIa unable to bind to
the capture antibody but would have no effect upon the
activity assay. An alternative hypothesis is that the assay
specificity using the sTF activity assay is not absolute and
TF-independent activation of FVII by FXa can occur
(Neuenschwander & Morrissey, 1992). Activation of FVII
by the sTFFVIIa complex can also occur under certain
reaction conditions (Fiore et al, 1994). Clearly, if even a
small proportion of the FVII is activated, the specificity of the
assay would be reduced as the zymogen is present in great
molar excess.

Table II. Prevalence of inherited bleeding disorders

in differing populations (excluding von Willebrands
disease) (Peyvandi, 2000).

en

692

Fig 2. Spectrum of bleeding problems in patients with inherited

deficiencies of factor VII (Peyvandi et al, 1997). Factor
VII:C < 10 l/dl.

2002 Blackwell Science Ltd, British Journal of Haematology 118: 689700

Review
1998). In patients with mildmoderatesevere disease,
epistaxes and gum bleeding, menorrhagia and other
mucous membrane-type bleeding is common. Menorrhagia
and chronic iron deficiency is common in women with
factor VII deficiency. These mucosal-type bleeding patterns
are similar to those seen in patients with inherited disorders
of platelet function. The explanation for the mucosal-type
bleeding in FVII deficiency is unclear, although a prolongation of the bleeding time has been reported (Bernardi et al,
1994).
In patients with severe factor VII deficiency, bleeding into
the central nervous system is common and reported in
between 15% and 60% of cases (Peyvandi et al, 1997;
Mariani et al, 1998). Such cases often present shortly after
birth and this presentation is associated with a high
morbidity and mortality.
Joint bleeds have been reported in patients with factor VII
deficiency (Peyvandi et al, 1997; Mariani et al, 1998) and,
in one of these studies, the severity of haemarthroses and
the long-term sequelae was similar to that seen in haemophilia (Mariani & Mazzucconi, 1983). However, haemarthroses are not a consistent finding and other studies have
failed to identify this as a common problem in patients with
severe FVII deficiency (Peyvandi et al, 1997).
Factor VII knockout mouse
The current theory of blood coagulation in man suggests
that a failure to initiate coagulation through the binding of
tissue factor to factor VII is likely to be incompatible with
life. This theory is supported by the FVII knockout mouse
which, although developing normally to term, dies shortly
at/or after birth from major abdominal and intracranial
haemorrhage (Rosen et al, 1997). Furthermore, of the
mutations that have been reported within the human
factor VII gene, there has until recently been a complete
absence of any mutation that one could confidently predict
would result in failure of factor VII production (see http://
europium.csc.mrc.ac.uk/usr/WWW/WebPages/FVII/database). McVey et al (1998) have reported a 5 splice site
mutation within intron 4 of the FVII gene that leads to a
deletion of exon 4 from FVII mRNA. Subsequent in vitro
expression studies failed to demonstrate production of FVII
protein and the authors concluded that the presence of this
homozygous mutation in the index case led to a complete
absence of FVII in the plasma. The child described by McVey
et al (1998) presented at the age of 10 d with massive
intracerebral haemorrhage from which he subsequently
died 2 d later. In addition, within the same family, a baby
girl from a previous pregnancy died at the age of 1 month
with cerebral haemorrhage and hydrocephaly. It seems
probable that she had an identical genotype/phenotype to
explain her symptoms. However, Peyvandi et al (2000b)
recently reported the case of a 5-year-old male of Chinese
origin who was diagnosed with severe FVII deficiency at the
age of 3 years when he presented with recurrent bleeding
problems haematuria, haemarthroses, muscle and soft
tissue haematomas, and bleeding from the gastrointestinal
tract. Many of these bleeding problems were spontaneous or
occurred in relation to minor trauma. Investigations

693

showed a prolonged prothrombin time and markedly

reduced plasma factor VII activity and antigen levels in
plasma at > 0001 l/ml consistent with severe factor VII
deficiency. The child was treated initially with fresh-frozen
plasma and subsequently with FVII concentrates and, to
date, remains well. Mutational analysis identified a homozygous 2 bp deletion (nucleotides 27/28: CT) within exon
1a of the FVII gene at codon )52/51, a region that encodes
part of the prepro-peptide of FVII. Sequence analysis of both
parents confirmed that they were both heterozygous for this
2 bp deletion mutation. This mutation results in a frameshift, the creation of a premature stop codon and the
complete absence of any circulating factor VII. The explanation for the differences in the natural history of this case
and that reported by McVey et al (1998) is unclear, but the
former case clearly indicates that a complete absence of FVII
is compatible with life. The lack of correlation between
in vitro FVII:C values and the clinical phenotype may reflect
the finding that only trace amounts of FVIIa are required to
initiate coagulation in vivo. In vitro assays fail to differentiate
between a true
null mutation and one that yields very low
but not zero FVII:C levels.
FVII deficiency and thrombosis
Thrombosis in association with factor VII deficiency has
been reported (Gershwin & Gude, 1973; Ben Dridi et al,
1986; Escoffre et al, 1995; Kang et al, 1998) although the
mechanism is unclear. One can speculate that, in some
cases, the underlying mutation may be one that leads to
different FVII:C results with differing thromboplastins and
that the patient does not have true FVII deficiency but an
unusual variant similar to that seen with Factor VII
Padua (Girolami et al, 1978). In such cases, the diagnosis of
factor VII deficiency is misleading and other risk factors for
thrombosis become more important. An alternative hypothesis to explain the association between factor VII deficiency and thrombosis is that the mutation giving rise to the
deficient phenotype results in a factor VII molecule that fails
to bind TFPI and, therefore, the TFVIIa initiation pathway
of coagulation remains active.
A reduction in FVII levels has also been reported in
association with hyperhomocysteinaemia (Munnich et al,
1983; Palareti & Coccheri, 1989) and, in at least one study,
normalized after patients were placed on a low methionine
diet supplemented with betaine (Munnich et al, 1983).
Abnormalities of the other vitamin K-dependent clotting
factors have not been reported. The low FVII levels in
hyperhomocysteinaemia has also been suggested as a
possible mechanism to explain the rare cases of apparent
factor VII deficiency associated with thrombosis (Munnich
et al, 1983).
To date, mutational analysis in families with inherited
FVII deficiency associated with thrombosis has not been
reported and any proposed mechanism remains speculative.
Elevated levels of factor VII also appear to play an
important role in atherothrombotic heart disease. Data
from the Northwick Park Heart Study suggests that factor
VII levels in the upper part of the normal distribution
are an independent risk factor for the development of

2002 Blackwell Science Ltd, British Journal of Haematology 118: 689700

694

Review

cardiovascular disease (Meade et al, 1986). Plasma FVII

levels also increase with age, female sex and hyperlipidaemia, especially hypertriglyceridaemia (Simpson et al,
1983). There are also a number of polymorphisms within
the FVII gene that can influence FVII levels and these have
been described in an earlier section.
Elevated factor VII levels as a risk factor for venous
thromboembolic disease have been evaluated as part of the
Leiden Thrombophilia Study (Koster et al, 1994). The
authors studied 199 unselected patients aged < 70 years
with a first objectively proved deep vein thrombosis (DVT)
and without known malignancy. Although they were able
to demonstrate a relationship between factor VII levels and
various F7 gene polymorphisms, they failed to show any
correlation between factor VII levels and thrombotic risk.
INHERITED FACTOR VII DEFICIENCY
In the last 5 years there has been an explosion in the
number of cases of FVII deficiency reported in the literature.
The factor VII mutation web site (http://europium.csc.mrc.ac.uk/usr/WWW/WebPages/FVII/database)
currently lists 120 mutations scattered throughout the
factor VII gene and these are summarized in Table III. The
majority of the mutations are located within the catalytic
domain of factor VII, emphasizing the functional importance of this region. However, mutations are located
throughout the gene, suggesting that all domains are
important in maintaining the overall structure and function
of factor VII. In common with many diseases, numerous
examples of repeated mutations within the factor VII gene
have been reported, but these are not shown in Table III. In
a number of studies, haplotyping has shown that identical
haplotypes co-segregate with identical mutations, suggesting a founder-effect rather than an independent origin for
the mutation (Bernardi et al, 1993; Wulff & Herrmann,
2000).
To date, only a relatively small number of factor VII
mutations have been expressed in vitro and, therefore, the
mechanism by which many mutations result in the disease

phenotype is unclear. Structural modelling has been used to

try and predict the effects of specific mutations but such
predictions remain speculative (Peyvandi et al, 2000c).
Peyvandi et al (2000c) analysed the FVII gene in 27
patients with FVII deficiency from 21 unrelated families
predominantly of Middle-Eastern extraction. A total of 19
different mutations were identified, of which 12 were novel
and 7 had been previously reported. Nine of the 12 novel
mutations were missense mutations located in the
Gla domain (Ser23Pro), the second epidermal growth factor
domain (Cys135Arg) and the catalytic serine protease
domain (Arg247Cys, Arg277Cys, Ser282Arg, Pro303Thr,
Ser363Ile, Trp364Cys, Trp364Phe), of which five were
homozygous. Three novel splice mutations were identified
in intron 1a (IVS1a+5), intron 2 (IVS2+1) and intron 6
(IVS6+1). Conformational analyses of crystal structures for
FVIIa and the FVIIatissue factor complex provided likely
explanations for the effect of the missense mutations on
FVIIa secretion or function (Fig 3A and B). In particular,
the majority of the missense mutations were located on the
serine protease domain, mostly to the region between the
catalytic triad and the contact surface with tissue factor,
indicating that orientation of the serine protease domain
relative to bound tissue factor in the complex is crucial for
functional activity.
ACQUIRED FACTOR VII DEFICIENCY
Acquired deficiencies of vitamin K are seen in a wide variety
of disorders but most are secondary to liver disease or
vitamin K antagonists. Dicoumarol is a naturally occurring
vitamin K antagonist and Warfarin (4-hydroxy-coumarin)
the synthetic anticoagulant, although both have similar
effects upon coagulation. Warfarin inhibits two vitamin
K-dependent enzymes within the liver a vitamin
K-dependent reductase and a vitamin K-dependent quinone
reductase. This prevents efficient recycling of vitamin K to
its enzymatically active form and limits the activity of a
vitamin K-dependent carboxylase. Other vitamin K antagonists include Acenocoumarol (
Sinthromin) and Phenprocoumon (
Marcoumar). Warfarin is the most widely used
oral anticoagulant in the USA and UK but Acenocoumarol

Table III. Summary of Factor VII gene mutations.

Mutation type

Number reported

Promoter mutations
Splice-type mutations
Nonsense mutations
Missense mutations
Insertions/deletions
Location of mutation
Promoter region
Pre-pro-leader sequence
Gla domain
EGF-1 domain
EGF-2 domain
Activation region
Catalytic domain

6
17
6
77
14
6
9
7
9
10
8
61

Fig 3. (A) Ribbon view of the crystal structure of the complex

between FVIIa and TF. The a-carbon atoms of the novel mutations
identified in the study of Peyvandi et al (2000c) are shown in yellow
and previously identified mutations in blue. The catalytic triad is
represented by spheres and shown in red; the Gla domain in dark
grey; the EGF-1 and EGF-2 domains in green; and the N-terminal
and C-terminal serine protease (SP) subdomains in light grey and
magenta respectively. The two fibronectin type III domains in tissue
factor are identified in brown. (B) Ribbon view of the main-chain of
the catalytic serine protease domain of FVIIa. The a-carbon atoms
of the catalytic triad H193, D242 and S344 are shown as red
spheres at the interface between the two subdomains of the serine
protease (SP) domains, shown in light grey (SP1) and magenta
(SP2) respectively. Novel mutations identified in the study of
Peyvandi et al (2000c) are shown in yellow and previously identified mutations in blue.

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2002 Blackwell Science Ltd, British Journal of Haematology 118: 689700

695

696

Review

and Phenprocoumon are popular in other countries.

Phenindione is an indiandione derivative rather than a
4-hydroxy derivative, although it appears to inhibit vitamin
K reductases in a similar manner to the coumarins.
In patients with chronic liver disease, the levels of factor
VII are often disproportionately lower than other vitamin
K-dependent factors, e.g. prothrombin and factor X
(Mammen, 1994). Other hepatic disorders, e.g. Dubin
Johnson syndrome, Rotor syndrome and Gilberts syndrome
may be associated with lowered factor VII levels (Roberts &
Lefkowitz, 1998). The clotting abnormalities in liver disease
are multifactorial and outwith the scope of this review.
A defect affecting all the vitamin K-dependent clotting
factors has been reported and shown to be due to a
mutation within the gamma-glutamyl carboxylase gene
(Spronk et al, 2000). These rare cases often respond to
supplementation of the diet with oral vitamin K.
Rare cases of factor VII deficiency secondary to drugs
other than oral anticoagulants, e.g. penicillins (Mehta et al,
1992) and the cephalosporins (Kaiser et al, 1991) have
been reported. Acquired factor VII inhibitors have also been
reported occurring either spontaneously (Meade, 1988;
Ndimbie et al, 1989; de Raucourt et al, 1994; Kamikubo
et al, 2000) or in association with other diseases, e.g.
myeloma (Elezovic et al, 1989). Factor VII deficiency has
been reported in association with an underlying malignancy (de Raucourt et al, 1994), in patients with sepsis
(Biron et al, 1997), in association with the use of antithymocyte globulin (Fischer et al, 1985), in patients
receiving interleukin 2 (IL-2) therapy (Birchfield et al,
1992) and in patients with aplastic anaemia (Weisdorf
et al, 1989).
MANAGEMENT OF FACTOR VII DEFICIENCY
Inherited factor VII deficiency
Inherited factor VII is a rare disorder and there are no
generally agreed guidelines for the management of this
disorder. For children and previously untreated adults with
moderatesevere FVII deficiency, recombinant factor VIIa
(rVIIa) is probably the treatment of choice.
Plasma FVII has a short in vivo half-life of approximately
5 h although this may be shorter during a bleeding episode
(Lindley et al, 1994). In contrast to deficiencies of factor VIII
and IX in which a therapeutic level of 100 l/dl is often
required, efficient haemostasis even during surgery can be
achieved with levels of FVII in the range of 1015 l/dl
(Triplett, 1977; Zimmermann et al, 1979; Kelleher et al,
1986; Saint-Raymond et al, 1989).
Current therapeutic options to treat inherited FVII
deficiency include fibrinolytic inhibitors, plasma, intermediate purity factor IX concentrates (prothrombin complex
concentrates), factor VII concentrate and recombinant VIIa
(rVIIa).
Plasma
The content of factor VII in normal plasma is, by definition
100 U/dl. Although plasma has been widely used in the
management of factor VII deficiency, there is little informa-

tion available on its efficacy. Plasma has been successfully

used to manage patients undergoing various surgical
operations either by itself or in combination with FVII
concentrate (Greene & McMillan, 1982; Doran et al, 1994).
However, in cases in which prolonged administration is
required and because of the short half-life of FVII, it is often
difficult to administer sufficient plasma quickly enough and
problems with fluid overload may be encountered (Briet &
Onvlee, 1987). If plasma is used to treat FVII deficiency it is
sensible to use a virally inactivated plasma to minimize the
risk of transfusion-transmitted disease.
Factor IX concentrates and prothrombin complex concentrates
Intermediate purity factor IX concentrates (prothrombin
complex concentrates), i.e. concentrates that are not
produced by either monoclonal or recombinant techniques,
contain variable amounts of factor VII and have been
successfully used to manage patients with factor VII
deficiency (White et al, 1979; Sumi et al, 1985). The
amount of factor VII in each of these concentrates is very
variable but is usually indicated by the manufacturer and
this can then be used to calculate the amount required for
replacement therapy. Many of these intermediate purity
factor IX concentrates contain activated forms of factors VII,
IX and X and should be used with caution, as there are
reports of both venous and arterial thromboses associated
with their use (Gershwin & Gude, 1973; Nakagawa et al,
1990; Schulman et al, 1991; Escoffre et al, 1995). For these
reasons, it is also unwise to use these concentrates in the
presence of liver disease, in cases of major trauma, or in
neonates whose livers are relatively immature.
Factor VII concentrates
A number of plasma-derived factor VII concentrates have
been developed and have been successfully used to manage
patients with inherited factor VII deficiency with spontaneous bleeding episodes or undergoing a wide variety of
surgical procedures (Mariani et al, 1978; Dike et al, 1980;
Gagliardi et al, 1983; Sumi et al, 1985; Eikenboom et al,
1992; Robertson et al, 1992; Rivard et al, 1994). Factor
VII concentrates have also been successfully used for
prophylaxis against bleeds in children with severe factor
VII deficiency and suggested guidelines for the administration of factor VII for long-term prophylaxis are in the
range of 1050 U/kg one to three times a week. Although
this seems illogical when one considers the short half-life
of factor VII, in practice it seems successful (Cohen et al,
1995). For surgery, doses ranging from 8 to 40 U/kg every
46 h have been successfully used (Schricker & Neidhardt,
1981; Greene & McMillan, 1982; Gagliardi et al, 1983;
Sumi et al, 1985; Ferster et al, 1993). Careful monitoring
of patients receiving FVII concentrates is essential to
prevent excessively high peaks and troughs. For major
surgery, trough factor VII levels should not fall below
20 U/dl.
Recombinant factor VIIa (rVIIa)
A number of studies have shown that patients with FVII
deficiency can be safely managed using rVIIa. Recombinant

2002 Blackwell Science Ltd, British Journal of Haematology 118: 689700

Review
FVIIa probably has a shorter half-life than that of plasma
FVII (Thomsen et al, 1993; Lindley et al, 1994), particularly
in children in whom an increased clearance has been
demonstrated (Lusher et al, 1998; Schulman, 1998) and in
pregnancy (Jimenez-Yuste et al, 2000). In such situations,
more frequent dosing or a continuous infusion may be
required to maintain haemostatically active FVII levels.
Mariani et al (1999) reported their experience with
rVIIa in treating 17 patients with 27 spontaneous bleeding episodes who, in addition, also underwent 7 major and
13 minor surgical procedures (Mariani et al, 1999). The
majority of the patients were severely deficient patients
with FVII levels of < 1%. Fifteen haemarthroses were
treated with only a single dose of rVIIa (1430 lg/kg) and
in only one case was rVIIa ineffective. Seven major
surgical procedures were performed in severely affected
patients under cover of rVIIa and no bleeding occurred
either during or after surgery. In the case of surgery, rVIIa
was given at 23 h intervals for the first 24 h followed by
longer intervals (38 h) for the remaining post-operative
period. All the surgical patients also received tranexamic
acid along with the rVIIa. In one patient, the drug was
ineffective following the development of an anti-FVII
antibody.
Several other groups have reported the successful use of
rVIIa with a variety of clinical problems (Ingerslev et al,
1997; Scharrer, 1999; White et al, 2000; Wong et al,
2000). In general, a dose of 2025 lg/kg administered
every 46 h appears to be successful in treating the
majority of patients with FVII deficiency who are either
bleeding or who require treatment prior to and following
surgery. The duration of treatment is very much dependent
upon the indication for treatment but, at least in some
cases, a single dose may be effective. In patients receiving
20 lg/kg of rVIIa every 6 h, this leads to peak FVII levels of
4383 U/ml and trough levels of 03 U/ml. Inhibitors
following treatment with rVIIa have been reported (Bauer,
1996).
Continuous infusion of rVIIa has been used in at least one
patient with moderate factor VII deficiency (VII:C 37 U/dl)
to provide haemostatic cover for an elective caesarean
section (Jimenez-Yuste et al, 2000). Pharmacokinetic studies performed prior to the infusion revealed a very high
clearance rate (0208 l/h/kg) and a short half-life
(0884 h), which the authors attributed to the pregnancy.
The patient received an initial bolus or rVIIa of 133 lg/kg
followed by a continuous infusion initially at a rate of
33 lg/kg/h for 48 h and then at 166 lg/kg/h for a further
48 h. Plasma factor VII and VIIa levels were maintained
between 1 and 15 U/ml and no bleeding problems were
observed.
Acquired factor VII deficiency
Acquired factor VII deficiency, together with deficiencies of
the other vitamin K-dependent clotting factors, is most
commonly seen in patients receiving coumarin anticoagulant (commonly warfarin) therapy. In major life-threatening
bleeds, prompt reversal of these anticoagulants can be
achieved using prothrombin complex concentrates (Makris

697

& Watson, 2001). Fresh-frozen plasma has also been used to

treat patients with bleeding secondary to oral anticoagulant
therapy, although there are concerns that the International
Normalized Ratio (INR) is not sensitive to changes in factor
IX that may be important in determining the outcome of a
bleeding episode (Makris & Watson, 2001). A comprehensive review of the management of over-anticoagulation
secondary to coumarins has recently been published
(Makris & Watson, 2001).
In patients with factor VII deficiency secondary to liver
disease, the use of prothrombin complex concentrates is
contraindicated because of the risks of thrombosis. In
such patients, fresh-frozen plasma, desmopressin, vitamin
K and platelets may be used to treat the coagulopathy.
Recombinant factor VIIa (rVIIa) has been used successfully to treat the coagulopathy secondary to advanced
cirrhosis (Bernstein, 2000) and may be a therapeutic
option in patients who fail to respond to other treatment
modalities.
Isolated factor VII deficiency in association with other
disorders is rare. In general, only case reports exist in the
literature and there is no consensus as to how such
patients should be managed. Treatment or removal of the
underlying cause, if this can be identified, is clearly
important. In patients who are actively bleeding, the use
of factor VII concentrates or rVIIa may be of value.
Similarly, in such rare cases the use of intravenous
immunoglobulin and immunosuppressive agents may be
of value. Finally, fibrinolytic inhibitors, e.g. Tranexamic
acid and fibrin glue, may be helpful in promoting and
securing haemostasis.
Haemophilia Centre and
Haemostasis Unit, Royal Free and
University College Medical School,
London, UK

D AVID J. P ERRY

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Keywords: factor VII, bleeding diathesis, mutations,

treatment, assays.

2002 Blackwell Science Ltd, British Journal of Haematology 118: 689700