BACKGROUND

Summary
Disease characteristics.  Factor V Leiden thrombophilia is
characterized by a poor anticoagulant response to activated protein C
(APC) and an increased risk of venous thromboembolism. The term
"factor V Leiden" refers to the specific G-to-A substitution at
nucleotide 1691 in the gene for factor V that predicts a single amino
acid replacement (Arg506Gln) at one of three APC cleavage sites in the
factor Va molecule. Factor V Leiden is inactivated at a rate
approximately ten times slower than normal factor V and persists
longer in the circulation, resulting in increased thrombin generation
and a mild hypercoagulable state reflected by elevated levels of
prothrombin fragment F1+2 and other activated coagulation markers.
Individuals heterozygous for the factor V Leiden mutation have a
slightly increased risk for venous thrombosis; homozygous individuals
have a much greater thrombotic risk.

Diagnosis/testing.  The diagnosis of factor V Leiden thrombophilia is
suspected in individuals with a history of venous thrombosis or in
families with a high incidence of venous thrombosis. The diagnosis of
factor V Leiden thrombophilia is made either using a coagulation
screening test or by DNA analysis of the F5 gene, which encodes the
factor V protein.

Genetic counseling.  Heterozygosity for the factor V Leiden allele and
the associated risk for venous thrombosis are inherited in an
autosomal dominant manner. Homozygosity for the factor V Leiden allele
and a much greater risk for venous thrombosis are inherited in an
autosomal recessive manner. Because of the high prevalence of the
factor V Leiden allele in the general population, the genetic status
of both parents and/or the spouse of an affected individual needs to
be evaluated before information regarding potential risks to sibs or
offspring can be provided. Prenatal testing is not routinely available
or utilized because factor V Leiden thrombophilia is a relatively mild
disorder and effective therapy is available.

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Diagnosis

Clinical Diagnosis
Although no clinical features are specific for factor V Leiden
thrombophilia, the diagnosis is suspected in individuals with a
history of venous thromboembolism (VTE) [deep vein thrombosis (DVT) or
pulmonary embolism], especially in women with a history of VTE during
pregnancy or in association with oral contraceptive use, and families
with a high incidence of VTE.

There is growing consensus that testing for factor V Leiden should be
performed in the following circumstances [ACMG Consensus Statement2001
, CAP Consensus Conference Statement 2002]:

A first VTE before 50 years of age
A first unprovoked VTE at any age
Recurrent VTE
Venous thrombosis at unusual sites (such as cerebral, mesenteric,
portal, and hepatic veins)
VTE during pregnancy, the puerperium, or in association with oral
contraceptive use or hormone replacement therapy
A first VTE and a strong family history of VTE. [Note: No consensus or
universally accepted definition of "strong family history" has been
developed.]
Testing for factor V Leiden may also be considered for the following
individuals:

Asymptomatic adult family members of probands with a known factor V
Leiden mutation, especially those with a strong family history of VTE
at a young age
Asymptomatic female family members of probands with known factor V
Leiden who are pregnant or are considering oral contraceptive use or
pregnancy
Women with unexplained pregnancy loss during the second or third
trimester
Selected women with unexplained severe preeclampsia, placental
abruption, or intrauterine growth retardation
Women with a first VTE related to tamoxifen or other selective
estrogen receptor modulators (SERM)
Female smokers under 50 years of age with a myocardial infarction
Individuals older than 50 years of age with a first provoked VTE in
the absence of malignancy or of an intravascular device
Factor V Leiden testing is not recommended:

As a general population screen
As a routine initial test during pregnancy or prior to the use of oral
contraceptives, hormone replacement therapy, or SERM
As a prenatal or newborn test, or as a routine test in asymptomatic
children
As a routine initial test in individuals with arterial thrombosis.
However, testing may be considered in selected young individuals (<50
years of age) with unexplained arterial thrombosis in the absence of
other risk factors for atherosclerotic vascular disease.
Testing
The diagnosis of factor V Leiden thrombophilia is made either by the
APC resistance assay as a coagulation screening test or by DNA
analysis of the factor V gene (F5). Factor V Leiden is inactivated at
a rate approximately ten times slower than normal factor V and
persists longer in the circulation, resulting in increased thrombin
generation and a mild hypercoagulable state, reflected by elevated
levels of prothrombin fragment F1+2 and other activated coagulation
markers [Martinelli et al 1996 , Zoller et al 1996].

The APC resistance assay is a coagulation screening test based on the
aPTT; two versions are available.

The "original" APC resistance assay involves performing an aPTT on the
individual's plasma in the presence and absence of a standardized
amount of exogenous APC; the two results are expressed as a ratio
(aPTT + APC/ aPTT - APC). This assay is based on the principle that
when added to normal plasma, APC inactivates factors Va and VIIIa,
which slows coagulation and prolongs the aPTT. The APC resistant
phenotype is characterized by a minimal prolongation of the aPTT in
response to APC and a corresponding low ratio. The original assay has
a sensitivity and specificity of 85-90% for factor V Leiden. Its
limitations are that it cannot be used in individuals with a baseline
prolonged aPTT due to warfarin or heparin anticoagulation, other
coagulation defects, or a lupus inhibitor, and it may be altered by
the hemostatic changes that occur during pregnancy or acute
thrombosis.
The modified ("second-generation") APC resistance assay overcomes
these limitations, is now more widely available, and has a sensitivity
and specificity for factor V Leiden approaching 100% [Jorquera et al
1994 , Kapiotis et al 1996]. In this assay, the individual's plasma is
first diluted (1:4) in factor V-deficient plasma that contains a
heparin neutralizer polybrene. The addition of the factor V-deficient
plasma corrects for deficiencies of all other coagulation proteins,
neutralizes therapeutic concentrations of heparin, and also eliminates
the effect of some lupus inhibitors. The assay can be used for
individuals receiving warfarin or heparin anticoagulation and for many
individuals with lupus inhibitors, as well as in the setting of acute
thrombosis, pregnancy, or inflammation [Svensson et al 1997].

Molecular Genetic Testing
GeneReviews designates a molecular genetic test as clinically
available only if the test is listed in the GeneTests Laboratory
Directory by at least one US CLIA-certified laboratory or a clinical
laboratory outside the US. GeneTests does not independently verify
information provided by laboratories and does not warrant any aspect
of a laboratory's work; listing in GeneTests does not imply that
laboratories are in compliance with accreditation, licensure, or
patent laws. Clinicians must communicate directly with the
laboratories to verify information. —ED.

Gene.   F5 is the only gene associated with factor V Leiden
thrombophilia.

Molecular genetic testing: Clinical method

Mutation analysis.  The most common DNA-based test involves RFLP
analysis of the F5 gene. The factor V Leiden mutation destroys an Mnl
I restriction endonuclease recognition site, allowing the factor V
Leiden mutant allele to be distinguished from the normal factor V
allele by the change in RFLP pattern.

Table 1. Molecular Genetic Testing Used in Factor V Leiden
Thrombophilia  Test Method Genetic Mechanism Mutation Detection Rate
Test Availability
Mutation analysis G-to-A substitution at nucleotide 1691 in the F5
gene 100%  Clinical
 

Testing Strategy for a Proband
When appropriate clinical care requires testing for the factor V
Leiden allele, either direct DNA-based genotyping or a factor V
Leiden-specific functional assay is recommended. Although the modified
APC resistance assay is highly sensitive and specific for the factor V
Leiden mutation, DNA-based testing for the factor V Leiden allele is
often used in individuals with:
A low value based on the original APC resistance assay, in order to
distinguish between factor V Leiden and other causes of APC resistance
Strong lupus inhibitors and a markedly prolonged baseline aPTT
Very low second-generation APC resistance assay values, in order to
differentiate heterozygotes, homozygotes, and "pseudohomozygotes" who
are heterozygous for both factor V Leiden and a second mutation
causing a factor V deficiency
Borderline APC resistance assay values
Individuals who test positive by a functional assay should then be
further studied with the DNA test for confirmation and to distinguish
heterozygotes from homozygotes.
Individuals on heparin therapy or with known lupus anticoagulant
should proceed directly to molecular genetic testing if the modified
functional assay is not used.
When relatives of individuals known to have factor V Leiden
thrombophilia are tested, the DNA method is recommended [ACMG
Consensus Statement 2001].
Clinical Description
The primary clinical manifestation of factor V Leiden thrombophilia is
venous thromboembolism (VTE). The most common site for deep venous
thrombosis (DVT) is the legs, although superficial venous thrombosis
can also occur. Presence of the factor V Leiden allele has also been
reported in individuals with central retinal vein occlusion, cerebral
sinus thrombosis, and hepatic vein thrombosis. A significant fraction
of individuals with venous leg ulcerations have APC resistance and the
factor V Leiden allele [Larsson et al 1996 , Munkvad & Jorgensen 1996
, Zuber et al 1996]. Multiple studies report that pulmonary embolism
is less common than DVT in individuals with the factor V Leiden allele
[Manten et al 1996 , Vandenbroucke et al 1998]. Analysis of pooled
data from these studies suggests that the prevalence of the factor V
Leiden allele in individuals with isolated pulmonary embolism is
approximately one half of that in individuals with DVT [de Moerloose
et al 2000]. Another study found that factor V Leiden heterozygotes
had a nearly eightfold lower incidence of DVT involving the
iliofemoral veins and significantly less extensive thromboses compared
to individuals without the mutation [Karemaker et al 2000 , de
Moerloose et al 2000]. This observation could account for the lower
risk of pulmonary embolism, as the iliofemoral veins are the most
common source of pulmonary emboli [Bjorgell et al 2000]. Two studies
found that heterozygosity for the factor V Leiden allele was not
associated with an increase in mortality or reduction in normal life
expectancy [Hille et al 1997 , Heijmans et al 1998].

The clinical expression of factor V Leiden thrombophilia is extremely
variable. Many individuals with the factor V Leiden allele never
develop thrombosis. Although most individuals with factor V
thrombophilia do not experience their first thrombotic event until
adulthood, some have recurrent thromboembolism before age 30 years.
The clinical expression is influenced by the number of factor V Leiden
alleles, the presence of coexisting genetic abnormalities, and
circumstantial risk factors.

The number of factor V Leiden alleles.   The relative risk of venous
thrombosis is increased approximately four- to eightfold in
individuals who are heterozygous for the factor V Leiden allele and up
to 80-fold in individuals who are homozygous. Although homozygotes
have a higher thrombotic risk and tend to develop thrombosis at a
younger age, the risk is much less than that associated with
homozygous protein C or S deficiency.

Presence of coexisting genetic abnormalities.   The presence of at
least one factor V Leiden allele increases the risk associated with
other inherited and acquired thrombophilic disorders, including
protein C, protein S, and antithrombin deficiencies, the prothrombin
gene mutation, and hyperhomocystinemia [Ridker, Hennekens et al 1997].
In general, the risk of thromboembolism increases exponentially in
individuals with more than one defect. For example, in the Physicians
Health Study, individuals with either at least one factor V Leiden
allele or hyperhomocystinemia had a three- to fourfold increased risk
of idiopathic thrombosis, but the relative risk increased 22-fold in
individuals with both abnormalities [Ridker, Hennekens et al 1997]. In
another study, individuals with either a single factor V Leiden allele
or prothrombin gene mutation had a four- to fivefold increase in
thrombotic risk, in contrast to double heterozygotes who had a 20-fold
increase in relative risk, illustrating the multiplicative effect of
these two factors on overall thrombotic risk [Emmerich et al 2001].

Circumstantial risk factors.   Other predisposing factors include age,
surgery, use of oral contraceptives, and pregnancy. These predisposing
factors are associated with the first thrombotic episode in at least
50% of individuals with a factor V Leiden allele. The risk increases
at a greater rate with advancing age in individuals with a factor V
Leiden mutation, also suggesting that thrombosis involves acquired, as
well as genetic, predisposing factors [Ridker, Glynn et al 1997]. In
the Physicians Health Study, a factor V Leiden allele was found in
nearly one third of men over age 60 years with an initial spontaneous
unprovoked thrombotic event. It is still unclear to what extent the
factor V Leiden mutation adds to the overall thrombotic risk in
individuals undergoing orthopedic surgery. In one study, individuals
with APC resistance had a fivefold increased risk of symptomatic
post-operative venous thromboembolism during the two months after
elective hip or knee replacement [Lindahl et al 1999]. In contrast, in
another study of individuals receiving standard prophylactic
antithrombotic therapy, the mutation was not associated with a
significantly increased risk of DVT during the immediate
post-operative period [Ryan et al 1998]. Several studies suggest that
a factor V Leiden allele increases the risk of central venous
catheter-associated thrombosis in individuals with malignancy or
undergoing bone marrow transplantation [Fijnheer et al 2002 , Mandala
et al 2004].

In a retrospective study of a large cohort of symptomatic factor V
Leiden homozygotes, the initial VTE was associated with circumstantial
risk factors in 81% of women and 29% of men. Oral contraceptives and
pregnancy were the most common predisposing factors in symptomatic
women. Thirteen percent of major surgeries were complicated by VTE,
suggesting a nearly 20-fold increase in risk. Leg trauma was
associated with a ninefold increased risk of a first VTE, which
occurred in 15% of factor V Leiden homozygotes compared to 1.8% of
control individuals without the mutation [Ehrenforth et al 2004].

Children.   Although venous thrombosis is far less common in children
than in adults, the prevalence of thrombophilic disorders in children
with thrombosis is higher than in a corresponding adult population. A
combination of risk factors appears to be required to provoke
thrombosis in pediatric patients [Rosendaal 1997 , Nowak-Gottl et al
2001]. An increased prevalence of a factor V Leiden allele was found
in neonates and children with venous thromboembolism in most, but not
all studies. APC resistance and a factor V Leiden allele were found in
21-52% of pediatric patients with venous thromboembolism in several
small series [Nowak-Gottl et al 1996 , Sifontes et al 1998]. A
heterozygous factor V Leiden mutation was found in 7.3% of unselected
Argentinean children with DVT or pulmonary embolism, compared to 2.4%
of controls, suggesting a three- to fourfold increase in thrombotic
risk [Bonduel et al 2002]. In contrast, another study of unselected
children with venous thromboembolism found a low prevalence of the
mutation, similar to that reported in the general population
[Revel-Vilk et al 2003]. The majority of the individuals reported had
other coexisting inherited and circumstantial risk factors in addition
to the factor V Leiden mutation. For example, in one study, 50% of
factor V Leiden heterozygotes had a coexisting thrombophilic disorder,
and circumstantial risk factors were present in all children with
venous thromboembolism. In a prospective study, asymptomatic
heterozygous and homozygous children who were family members of
symptomatic probands with the factor V Leiden mutation had no
thrombotic complications during an average follow-up period of five
years [Tormene et al 2002]. Thus, the available data suggest that
asymptomatic children with a factor V Leiden allele are at low risk
for thrombosis except in the setting of strong circumstantial risk
factors. Heterozygous and homozygous factor V Leiden mutations were
found in 29% and 2.3% of children with a first spontaneous venous
thrombosis, respectively. Children with a factor V Leiden mutation had
a four- to sixfold higher risk of recurrence, which occurred in 28% of
homozygotes and 19% of heterozygotes, compared to 5% of those with a
normal genotype [Nowak-Gottl et al 2001].

Arterial thrombosis.  The presence of a factor V Leiden allele is not
a major risk factor for arterial thrombosis. Most studies of
unselected adult populations found no association between presence of
a factor V Leiden allele and an increased risk of myocardial
infarction or stroke [Ridker, Hennekens et al 1995 ; Cushman et al
1998 ; Eskandari et al 1998]. A meta-analysis of 33 studies and
including 25,053 individuals found no significant association with
myocardial infarction, stroke, or peripheral vascular disease either
collectively or individually [Kim & Becker 2003]. However, some data
suggest that the factor V Leiden allele may contribute to arterial
thrombosis in younger individuals with other cardiovascular risk
factors. One study reported a significantly increased risk of
myocardial infarction in young women with other cardiovascular risk
factors, particularly smoking. Young women with a heterozygous factor
V Leiden mutation who smoked had a 30-fold increased risk of
myocardial infarction compared to women with neither risk factor
[Rosendaal et al 1997]. Several other studies found that the
simultaneous presence of prothrombotic mutations, including factor V
Leiden, and one or more cardiovascular risk factors substantially
increased the risk of acute myocardial infarction. The combination of
a prothrombotic mutation and smoking was associated with the highest
risk, with odds ratios ranging between six and 18 [Doggen et al 1998 ,
Inbal et al 1999]. Two studies found a significantly higher prevalence
of a factor V Leiden allele in young individuals with premature
myocardial infarction and normal coronary angiography, compared to
matched controls with significant coronary artery disease, with odds
ratios of 2.6 and 4.7, respectively [Mansourati et al 2000 , Van de
Water et al 2000]. In another study, the mutation was more frequent in
individuals with no flow-limiting stenosis after myocardial
infarction, compared to those with at least one stenotic vessel,
irrespective of age [French et al 2003]. Data also link factor V
Leiden thrombophilia to stroke in the pediatric population [Becker et
al 1998 , Kenet et al 2001]. The results of these studies suggest that
in certain selected populations, factor V Leiden thrombophilia may
contribute to the overall arterial thrombotic risk. Arterial
thromboembolism may also occur "paradoxically" through a patent
foramen ovale in the heart of individuals with venous thrombosis.
Arterial thrombosis may also occur prenatally in the fetus as a result
of placental venous thrombi entering the fetal circulation, crossing
the foramen ovale, and entering the cerebral arterial vasculature
[Thorarensen et al 1997].

Oral contraceptives, hormone replacement therapy, and selective
estrogen receptor modulators.  The use of oral contraceptives
substantially increases the risk of venous thromboembolism (VTE) in
women heterozygous for a factor V Leiden allele. A heterozygous
mutation is found in 20-35% of women with a history of venous
thrombosis during oral contraceptive use [Hellgren et al 1995 , Hirsch
et al 1996 , Schambeck et al 1997]. In the Leiden Thrombophilia study,
the risk of venous thrombosis was increased fourfold in oral
contraceptive users, and sevenfold in women with a heterozygous factor
V Leiden mutation. However, the risk was increased 35-fold in
heterozygous women who used oral contraceptives, indicating a
multiplicative rather than additive effect on overall thrombotic risk.
The adverse interaction between a factor V Leiden allele and oral
contraceptives was confirmed in other studies with odds ratios ranging
from 20 to 41 for the combination of both risk factors [Martinelli et
al 1999 , Legnani et al 2002]. The corresponding risk is increased
more than 100-fold in women homozygous for the factor V Leiden allele
who use oral contraceptives [Vandenbroucke et al 1994]. Women with
inherited thrombophilic disorders, such as factor V Leiden
thrombophilia, tend to develop thrombotic complications sooner, with a
much higher risk of thrombosis during the first year of oral
contraceptive use [Bloemenkamp et al 2000]. Oral contraceptives
containing the third-generation progestagen desogestrel are associated
with a twofold higher risk of venous thromboembolism than
second-generation preparations, with an especially high risk in factor
V Leiden heterozygotes. The risk was increased 50-fold in factor V
Leiden heterozygotes who used third-generation preparations containing
desogestrel, compared to women with no factor V Leiden allele not
using oral contraceptives [Bloemenkamp et al 1995].

Multiple studies have confirmed a significant (two- to fourfold)
increase in relative risk of VTE in current users of hormone
replacement therapy (HRT) compared to nonusers [Daly et al 1996 ,
Groodstein et al 1996 , Jick et al 1996 , Perez-Guthann et al 1997 ,
Hulley et al 1998 , Varas-Lorenzo et al 1998 , Grady et al 2000]. The
limited data available suggest that selective estrogen receptor
modulators (SERM) such as Tamoxifen and Raloxifene, are associated
with a similar increase in thrombotic risk [Fisher et al 1998 , Meier
& Jick 1998 , Cummings et al 1999]. Most of the observational studies
of HRT excluded women with known thrombophilia. Based on the known
interaction with estrogen, the use of HRT is expected to significantly
increase the risk of VTE in women with a factor V Leiden allele. In
one study, the combination of HRT use and activated protein C
resistance was associated with a 13-fold increase in relative
thrombotic risk compared to that found in women with neither risk
factor [Lowe et al 2000]. Reinvestigation of this same group of women
for prothrombotic mutations (factor V Leiden or the prothrombin gene
mutation) demonstrated a 15-fold increased risk of venous thrombosis
in HRT users with a heterozygous factor V Leiden mutation [Rosendaal
et al 2002]. In another study of postmenopausal women with coronary
heart disease, factor V Leiden heterozygotes who used HRT had a
14-fold higher thrombotic risk than nonusers without the mutation. The
estimated absolute incidence of VTE in women with coronary heart
disease and factor V Leiden who used HRT was 15 VTE events per 1000
women per year, compared to two VTE events per 1000 women per year for
non-users with a normal genotype [Herrington et al 2002]. The risk of
venous thromboembolism in women with factor V Leiden who use SERMS is
unknown, but likely higher than that associated with SERM alone. There
are several case reports of Tamoxifen-associated thrombosis in women
with factor V Leiden thrombophilia [Wietz et al 1997]. In light of the
increasing use of SERM in the treatment and prevention of breast
cancer and osteoporosis, factor V Leiden thrombophilia will likely be
shown to increase the risk of SERM-associated thrombosis in future
studies.

Pregnancy and thrombosis.  The available data suggest that the factor
V Leiden allele is associated with a sevenfold to 16-fold increase in
thrombotic risk during pregnancy and the puerperium. Resistance to
activated protein C was found in up to 60% of women with a history of
venous thromboembolism during pregnancy, compared to 10% of
nonpregnant women in a control group [Hellgren et al 1995]. Presence
of the factor V Leiden mutation was confirmed by DNA testing in 20% to
46% of women with pregnancy-associated venous thrombosis [Bokarewa et
al 1996 , Hirsch et al 1996 , Hallak et al 1997 , Grandone et al 1999
, Gerhardt et al 2000]. For example, in one recent study, factor V
Leiden thrombophilia was found in 44% of women with a history of
venous thrombosis during pregnancy, compared to 8% of matched
controls, with a corresponding ninefold increase in thrombotic risk.
The risk of thrombosis during pregnancy was increased more than
100-fold in women with both a factor V Leiden allele and the
prothrombin gene mutation, illustrating the marked increase in overall
risk when thrombophilic mutations are combined [Gerhardt et al 2000].
The risk of pregnancy-related VTE is increased 20- to 40-fold in women
with homozygous factor V Leiden [Martinelli et al 2001 , Gerhardt et
al 2003]. In one study of family members of symptomatic probands with
factor V Leiden thrombophilia, venous thrombosis occurred in 16% of
pregnancies in homozygous women compared to 0.5% of pregnancies in
unaffected relatives, conferring a 40-fold increase in relative
thrombotic risk [Martinelli et al 2001]. The prevalence of
pregnancy-related VTE was 9% in a series of unselected homozygous
women [Pabinger et al 2000].

Although presence of a factor V Leiden allele increases the relative
risk of VTE during pregnancy and the puerperium, the true risk in
asymptomatic heterozygotes is unknown. One prospective study screened
unselected pregnant women for presence of a factor V Leiden allele and
followed them throughout pregnancy. Thrombotic complications occurred
in only 1.1% of factor V Leiden heterozygotes [Lindqvist et al 1999].
In several retrospective studies, the estimated risk of VTE during
pregnancy and the puerperium in factor V Leiden heterozygotes was in
the range of one in 400 to 500 pregnancies [Bokarewa et al 1996 ,
McColl et al 1997]. The results of these studies suggest that although
factor V Leiden heterozygosity is an independent risk factor, the
absolute incidence of thrombosis during pregnancy is low. In contrast,
women with homozygous factor V Leiden or combined thrombophilia have a
much higher probability of VTE, in the range of one in 20 to one in
100 pregnancies [Martinelli et al 2001 , Gerhardt et al 2003].

Pregnancy loss.  In addition to the risk of venous thromboembolism
during pregnancy, accumulating evidence suggests that factor V Leiden
heterozygosity is associated with a small increase in the risk of
pregnancy loss, particularly after the first trimester. A large number
of case control studies consistently found a high prevalence of factor
V Leiden heterozygosity in women with unexplained recurrent pregnancy
loss (RPL) (up to 30%), compared to 1-10% of controls, with odds
ratios ranging from two to five [Grandone et al 1997 , Ridker et al
1998 , Brenner et al 1999 , Gris et al 1999 , Kupferminc et al 1999 ,
Martinelli et al 2000 , Younis et al 2000]. Several retrospective
cohort studies also found that factor V Leiden heterozygotes have a
significant (twofold) increased risk for RPL. In one study, factor V
Leiden heterozygotes had a twofold increased risk of stillbirth, but
no increased risk of miscarriage before 28 weeks' gestation [Preston
et al 1996]. In another study factor V Leiden heterozygotes had a
twofold increased risk of fetal loss by 20 weeks. Recurrent loss was
also two- to threefold more common in factor V Leiden heterozygotes.
Women with homozygous factor V Leiden had a twofold higher risk of
fetal loss than heterozygotes [Meinardi et al 1999]. Factor V Leiden
heterozygotes who are family members of probands with the mutation
have an approximately twofold increased risk of fetal loss after the
first trimester [Tormene et al 1999]. In one small prospective study,
miscarriage occurred in 11% of factor V Leiden heterozygotes compared
to 4.2% of women without a factor V Leiden allele [Murphy et al 2000].
In another prospective study, factor V Leiden heterozygotes with a
history of recurrent early miscarriage had a significantly lower live
birth rate than women with a similar history of unsuccessful
pregnancies but without the mutation. The live birth rate was 38% in
factor V Leiden heterozygotes compared to 69% in women with a normal
factor V genotype, suggesting that the mutation confers a three- to
fourfold higher risk of an adverse pregnancy outcome [Rai et al 2002].
However, a prospective follow-up study of thrombophilic women with no
prior history of pregnancy loss found that a factor V Leiden allele
conferred only a slight increase in risk of fetal loss (relative risk
1.4) [Vossen et al 2004]. In a meta-analysis including 3000 women, a
factor V Leiden allele significantly increased the risk of early first
trimester recurrent loss (odds ratio 2.1) and late recurrent and
non-recurrent loss (odds ratios 7.8 and 3.2, respectively) [Rey et al
2003]. Two other meta-analyses also found a strong association with
fetal loss [Dudding & Attia 2004 , Kovalevsky et al 2004].

Although most pregnancy losses occur in the first trimester, some
evidence exists that thrombophilic women have a higher risk of loss in
the second and third trimester. Four studies and three meta-analyses
suggest that factor V Leiden heterozygotes have a higher risk of late
pregnancy loss than early first trimester loss [Preston et al 1996 ,
Rai et al 1996 , Grandone et al 1997 , Tormene et al 1999 , Rey et al
2003 , Dudding & Attia 2004 , Kovalevsky et al 2004]. One possible
explanation is that late pregnancy losses may reflect thrombosis of
the placental vessels, in contrast to first trimester losses, which
are more commonly due to other causes. In several studies, the
majority of placentas from women heterozygous for factor V Leiden and
late fetal loss had evidence of thrombotic vasculopathy or infarction,
suggesting that RPL associated with presence of a factor V Leiden
allele is due to thrombosis [Gris et al 1999 , Martinelli et al 2000].
However, factor V Leiden thrombophilia also increases the risk of
early first trimester loss [Tal et al 1999 , Pihusch et al 2001 , Rey
et al 2003]. In one study, 35% of all fetal losses in factor V Leiden
heterozygotes were "pre-clinical" (prior to ultrasound confirmation of
fetal heart activity), compared to 12% of those in women without the
mutation [Tal et al 1999]. The pathophysiologic mechanisms responsible
for the association with early fetal loss are unclear. Maternal
thrombophilia could interfere with implantation or development of the
uteroplacental circulation, but there are no data confirming this. In
fact, a study of women who underwent in vitro fertilization found that
a factor V Leiden allele increased the likelihood of a successful
first embryo transfer, suggesting an advantage for implantation [Gopel
et al 2001].

Other pregnancy complications.  Although preeclampsia, fetal growth
retardation, and placental abruption may also involve impaired
placental perfusion, their association with factor V Leiden
thrombophilia remains controversial, with conflicting results from
different studies. Multiple case-control studies found a significantly
higher prevalence of factor V Leiden in women with preeclampsia
(8-26%) compared to women with normal pregnancies (2-10%) with odds
ratios ranging from two to five [Grandone et al 1997 , Grandone et al
1999 , Kupferminc et al 1999 , Agorastos et al 2002]. In contrast,
many other studies found no association of the mutation with
preeclampsia [Alfirevic et al 2001 , Livingston et al 2001 , Currie et
al 2002 , D'Elia et al 2002 , Morrison et al 2002]. A factor V Leiden
allele did not increase the risk of preeclampsia in two prospective
studies of unselected women screened at their first prenatal visit
[Lindqvist et al 1999 , Murphy et al 2000]. A meta-analysis of seven
case-control studies found a threefold increased risk of severe
pre-eclampsa [Dudding & Attia 2004].

The data on the risk of fetal growth retardation and placental
abruption are more limited, but also conflicting. A factor V Leiden
allele was found in 8-35% of women with fetal growth retardation
compared to 2-4% of control women, with odds ratios ranging from seven
to thirteen [Kupferminc et al 1999 , Martinelli et al 2001 ,
Kupferminc et al 2002]. Another study suggested that factor V Leiden
heterozygotes have a twofold higher risk of delivering a neonate with
fetal growth retardation [Grandone et al 2002]. In contrast, a larger
case control and other smaller studies found no significant
association between factor V Leiden and fetal growth retardation
[Alfirevic et al 2001 , Infante-Rivard et al 2002]. In two prospective
studies of unselected pregnant women, the mutation did not increase
the risk of fetal growth retardation [Lindqvist et al 1999 , Murphy et
al 2000]. Factor V Leiden was found in 22-30% of women with placental
abruption, compared to 3-6% of control women, with odds ratios ranging
from five to twelve [Wiener-Megnagi et al 1998 , Kupferminc et al 1999
, Facchinetti et al 2003]. Several other studies found no signficant
association [Lindqvist et al 1999 , Alfirevic et al 2001 , Prochazka
et al 2003]. These inconsistent results may reflect the varying
definitions of these complications, different ethnic groups and
selection criteria, and the small number of cases included.

The available data indicate that heterozygosity for factor V Leiden is
associated with a two- to threefold increase in relative risk of late
pregnancy loss, and possibly other complications, although the precise
risk is unknown and will require prospective longitudinal studies.
Although the mutation may contribute in some cases, the probability of
a successful pregnancy outcome is still high, and most factor V Leiden
heterozygotes never develop these serious obstetric complications.

Organ transplantation.  The prevalence of factor V Leiden in
individuals who have undergone renal transplantation is similar to
that in the general population, suggesting that it is not a risk
factor for developing end-stage renal disease (ESRD) [Wuthrich et al
2001]. However, recent evidence suggests that the mutation may
contribute to thrombotic and other complications after renal
transplantation [Kujovich 2004]. In several retrospective studies,
thromboembolic complications occurred in up to 39% of factor V Leiden
heterozygotes, compared to 6-15% of recipients without a factor V
Leiden allele [Irish et al 1997 , Wuthrich et al 2001]. The mutation
conferred an overall fourfold increased risk of graft vein thrombosis
and venous thromboembolism [Irish et al 1997]. Factor V Leiden has
been associated with both delayed graft function and early graft loss
[Wuthrich et al 2001 , Hocher et al 2002]. In one study, factor V
Leiden heterozygotes had a 12-fold higher risk of an early graft
perfusion defect, and a markedly increased risk of graft loss within
the first week (25%) compared to individuals with a normal genotype
(<1%) (odds ratio 64) [Wuthrich et al 2001]. Factor V Leiden
heterozygotes also had a significantly higher risk of graft loss
within the first year in some [Ekberg et al 2000 , Wuthrich et al
2001], but not all, studies [Pherwani et al 2003]. In the single study
that screened kidney donors, grafts from donors heterozygous for
factor V Leiden had a 30-day and one-year survival similar to those
from donors without the mutation [Pherwani et al 2003].

Factor V Leiden may also increase the risk of acute rejection after
renal transplantation. Several studies found that factor V Leiden
heterozygotes have a three- to fourfold higher risk of acute rejection
than those without the mutation [Ekberg et al 2000 , Hocher et al 2002
, Heidenreich et al 2003]. Although the number of individuals and
frequency of rejection varied, a consistent pattern of more frequent
rejection episodes was observed in recipients with a factor V Leiden
allele. A recent study of renal transplantation outcomes in 394 stable
recipients found that factor V Leiden heterozygotes were also
significantly more likely to develop chronic graft dysfunction,
reflected by both a steeper slope of the 1/creatinine-versus-time
curve, and a higher annual increase in the rate of urinary protein
excretion [Hocher et al 2002].

The contribution of factor V Leiden to thrombotic complications after
other types of organ transplantation is not well defined. There are
multiple cases of DVT and pulmonary embolism in recipients of a liver
transplant from donors heterozygous or homozygous for factor V Leiden
[Leroy-Matheron et al 2003 , Willems et al 2003]. A retrospective
study suggested that a liver transplant from a heterozygous donor was
associated with a twofold overall risk of post-operative venous or
hepatic vessel thrombosis [Hirshfield et al 1998]. In contrast, as
expected, heterozygosity for the mutation in recipients was not
associated with these thrombotic complications. Genetic diagnosis of
factor V Leiden acquired through liver transplantation requires
molecular analysis of donor tissue.

Genotype-Phenotype Correlations
Individuals homozygous for factor V Leiden have a tenfold higher risk
for thrombosis than heterozygotes. In one study, the risk of venous
thrombosis by age 33 years was twice as high in homozygotes as in
heterozygotes (40% vs 20%) [Zoller et al 1994]. However, the clinical
course of an acute thrombotic episode is not more severe or more
resistant to anticoagulation in homozygotes than in heterozygotes.

Severe APC resistance, reflected by a markedly reduced APC resistance
ratio, usually reflects homozygosity for the factor V Leiden mutation;
however, other genetic abnormalities may affect the expression of a
heterozygous factor V Leiden allele. One example is
"pseudo-homozygous" APC resistance, which occurs in individuals who
are heterozygous for the factor V Leiden mutation and have a low
factor V activity level measured in a coagulation assay. Rather than
attenuating the effect of the factor V Leiden mutation, a coexisting
factor V deficiency appears to enhance it, producing a more severe
APC-resistant phenotype, reflected by a extremely low APC resistance
ratio. Most of the individuals described have had a history of
thrombosis, but whether the thrombotic risk in "pseudo-homozygotes" is
as high as in factor V Leiden homozygotes is unclear, as few cases
have been reported.

Several different mutations associated with a quantitative factor V
deficiency have been described, including one polymorphism (the "R2
allele") found in up to 7.5% of the Italian population [Castaman et al
1997 , Castoldi et al 1998]. In rare cases, both a null allele and
factor V Leiden mutation occur on the same chromosome in cis
configuration. In these individuals, the resulting quantitative factor
V deficiency prevents expression of the factor V Leiden mutation
[Dargaud et al 2003].

A factor V gene haplotype (HR2) defined by the R2 polymorphism
(A4070G) may confer mild APC resistance and interact with the factor V
Leiden mutation to produce a more severe APC resistance phenotype
[Bernardi et al 1997 , de Visser et al 2000 , Mingozzi et al 2003]. In
one study, coinheritance of the HR2 haplotype increased the risk of
venous thromboembolism associated with factor V Leiden by
approximately threefold [Faioni et al 1999]. Whether the HR2 haplotype
alone is an independent thrombotic risk factor is still unclear. In
one study, the HR2 haplotype was associated with a twofold increase in
risk of venous thromboembolism [Alhenc-Gelas et al 1999]. In contrast,
several other studies found no significant increase in thrombotic risk
[de Visser 2000 , Luddington et al 2000].

A discrepancy between the APC resistant phenotype and factor V
genotype may occur in the setting of liver transplantation or stem
cell transplantation. Testing for the factor V Leiden mutation in
these settings is complicated by the primary hepatic synthesis of
factor V and other clotting factors, and the routine use of DNA
extracted from peripheral blood leukocytes in most factor V Leiden
assays. Individuals who aquired factor V Leiden and clinical and
laboratory evidence of resistance to APC have been reported after
liver transplantation [Leroy-Matheron et al 2003 , Willems et al
2003]. This type of "acquired factor V Leiden" is suggested by the
combination of an abnormal APC resistance screening assay and a normal
recipient factor V genotype. Genetic diagnosis of factor V Leiden
acquired through liver transplantation requires molecular analysis of
donor tissue. Discrepancies between APC resistance assays and factor V
genotype have also been reported in stem cell transplant recipients
[Camire et al 1998 , Crookston et al 1998]. These reports illustrate
the need to evaluate both APC resistance phenotype and factor V
genotype in order to accurately assess thrombotic risk in transplant
recipients.

Prevalence
Factor V Leiden thrombophilia is the most common inherited form of
thrombophilia. Heterozygosity for factor V Leiden occurs in 3-8% of
the general US and European populations. The frequency of homozygosity
for the factor V Leiden mutation is approximately one in 5000. The
prevalence varies considerably in different populations. The highest
heterozygosity rate is found in Europe; the mutation is extremely rare
in Asian, African, and indigenous Australian populations [Rees et al
1995]. The frequency of heterozygotes varies within Europe, with a
prevalence of 10-15% in southern Sweden and Greece and 2-3% in Italy
and Spain. In the US, heterozygosity for factor V Leiden was found in
5.2% of Caucasian Americans, 2.2% of Hispanic Americans, 1.2% of
African Americans, 0.45% of Asian Americans, and 1.25% of Native
Americans, reflecting the world distribution of the mutation [Ridker,
Miletich et al 1997].

The prevalence also depends on the particular population sampled, with
the factor V Leiden mutation present in approximately 15-20% of
individuals with a first DVT, and up to 50% of individuals with
recurrent venous thromboembolism or an estrogen-related thrombosis.

Differential Diagnosis
For current information on availability of genetic testing for
disorders included in this section, see GeneTests Laboratory
Directory. —ED.

APC resistance.  Although 95% of cases of APC resistance reflect the
presence of the factor V Leiden mutation, 5% of individuals have
repeatedly abnormal APC resistance tests in the absence of the factor
V Leiden allele. Depending on the screening assay used, some cases may
represent acquired APC resistance due to high factor VIII levels,
pregnancy, or a lupus anticoagulant effect. Two studies suggested that
APC resistance not caused by the factor V Leiden allele is also a risk
factor for venous thrombosis [de Visser et al 1999 , Rodeghiero &
Tosetto 1999]. In another study, resistance to APC was associated with
an increased risk of stroke and TIA, independent of the factor V
Leiden mutation [van der Bom et al 1996]. In rare cases, other genetic
abnormalities may produce an APC-resistant phenotype (see Molecular
Genetics).

Thrombophilic disorders.  The differential diagnosis of venous
thromboembolism includes several other inherited and acquired
thrombophilic disorders. As these thrombophilic disorders are not
clinically distinguishable, laboratory testing is required for
diagnosis in each case. Laboratory testing should be considered even
after the identification of the factor V Leiden allele, as it often
coexists with other disorders.

Inherited

The mutation 20210A in the 3' untranslated region of the gene encoding
prothrombin is found in 2% of the general population, 6% of
individuals presenting with a first DVT, and up to 18% of individuals
with a personal and family history of thrombosis. Coinheritance of
both a factor V Leiden allele and the prothrombin gene mutation occurs
in approximately one in 1000 in the general population and 2% of
individuals with venous thromboembolism [De Stefano et al 1999 ,
Emmerich et al 2001].
Inherited abnormalities or deficiencies of the natural anticoagulant
proteins C, S, and antithrombin are approximately tenfold less common
than the factor V Leiden allele.
Hereditary dysfibrinogenemias infrequently cause thrombophilia and
thrombosis.
Acquired

Homozygosity for the common polymorphism in the MTHFR gene is
associated with higher than normal levels of homocysteine, but in
general, measurement of the plasma concentration of homocysteine is
recommended rather than molecular genetic testing of the MTHFR gene.
The plasma concentration of homocysteine reflects genetic as well as
environmental factors and is more directly associated with thrombotic
risk.
Antiphospholipid antibodies (APA) are frequently identified in
individuals with a factor V Leiden allele, but can also cause APC
resistance in the absence of the factor V Leiden mutation. Some APA
may interfere with protein C activation by thrombin/thrombomodulin or
with APC-mediated degradation of FVa and FVIIIa, both of which are
phospholipid-dependent reactions. The acquired APC resistance
associated with APA should be distinguished from the spuriously low
APC resistance ratio that occurs in individuals with a prolonged aPTT
due to a lupus inhibitor.
A plasma concentration of factor VIII is a recognized independent risk
factor for venous thromboembolism, conferring a four- to sixfold
increase in risk in several studies [Margaglione et al 1999]. High
FVIII concentrations were also shown to significantly increase the
risk of recurrent thrombosis [Kyrle et al 2000].
Elevated plasma concentrations of factor IX and factor XI were also
linked to an approximately twofold increased risk of venous
thromboembolism [Meijers et al 2000 , van Hyickama et al 2000]. The
combination of oral contraceptives and high levels of prothrombin,
factor V or factor XI had a supra-additive effect on thrombotic risk,
with odds ratios ranging from ten to thirteen [van Hylckama Vlieg &
Rosendaal 2003]. However, it is still unclear whether assessment of
clotting factor concentrations should be included in a thrombophilia
evaluation [Kamphuisen et al 2001].
Other.   Although thrombosis has been reported in association with
abnormalities in other coagulation or fibrinolytic proteins such as
heparin cofactor II and PAI-1, a causal association has not been
established. Thus, testing for these abnormalities is not currently
recommended.

Management
Identification of other coagulation risk factors.  It is important to
evaluate an individual who has a factor V Leiden allele for other
inherited or acquired thrombophilic disorders. Such testing includes:
DNA testing for the prothrombin gene mutation (G-to-A substitution at
nucleotide 20210); measurement of total plasma concentration of
homocysteine; phospholipid-dependent coagulation assays for a lupus
inhibitor; serologic assays for anticardiolipin antibodies and in some
cases anti-beta 2 glycoprotein 1 antibodies; and in high-risk
individuals: 1) functional assays of protein C and antithrombin
activity; and 2) a free protein S antigen level or functional assay of
protein S activity.

Thrombosis.   The management of individuals with factor V Leiden
thrombophilia depends on the clinical circumstances. The first acute
thrombosis is managed routinely with a course of IV unfractionated
heparin or subcutaneous low molecular weight heparin (LMWH), followed
by oral administration of warfarin for three to six months. A target
international normalized ratio (INR) of 2.5 (therapeutic range two to
three) provides effective anticoagulation, even in individuals who are
homozygous for the factor V Leiden allele [Baglin et al 1998]. The
optimal duration of anticoagulation for individuals who are
heterozygous for the factor V Leiden allele is debated. Individuals
with either persistent risk factors or a spontaneous thrombosis with
no identifiable provoking factors require a longer course of
anticoagulation (e.g., six months or longer) than individuals with
temporary risk factors (such as surgery), who may safely receive a
shorter course of therapy [Schulman et al 1995 , Hirsh et al 1997]. It
is still unclear whether factor V Leiden heterozygosity increases the
risk of recurrent venous thromboembolism after a first episode. In
several studies, individuals with a heterozygous factor V Leiden
mutation had a two- to fourfold increased risk of recurrent thrombosis
during follow-up periods ranging from five to eight years [Ridker et
al 1995 , Simioni et al 1997 , Simioni et al 2000]. However, three
other studies found no significant difference in the rate of
recurrence between those with and without the mutation [Elchinger et
al 1997 , De Stefano et al 1999 , Lindmarker et al 1999]. Individuals
who are heterozygous for both factor V Leiden and the prothrombin gene
mutation or homozygous for factor V Leiden have a threefold to
ninefold higher risk of recurrence [De Stefano et al 1999 , Lindmarker
et al 1999 , Meinardi et al 2002]. The risk of recurrent VTE is four-
to fivefold higher in factor V Leiden heterozygotes with
hyperhomocysteinemia than in individuals with a factor V Leiden allele
alone [Meinardi et al 2002].

A double-blinded randomized trial compared three months versus two
years of warfarin anticoagulation in a large group of individuals with
a first spontaneous episode of venous thromboembolism [Kearon et al
1999]. Twenty-six percent of individuals were found to have the factor
V Leiden allele (92% of these were heterozygotes) on testing at the
time of enrollment. The trial was terminated early after interim
analysis showed a significantly higher rate of recurrent thrombosis in
individuals who completed only three months of anticoagulation
(17%/year) compared to those who continued warfarin (1.3%/year). In
the three-month treatment group, the presence of a factor V Leiden
allele was not a significant risk factor for recurrent thrombosis.
This study demonstrated that individuals with an initial spontaneous
thrombosis (with or without a factor V Leiden allele) require
anticoagulation for longer than three months, but whether they should
be treated for longer than six months is unknown.

Long-term oral anticoagulation should be considered in individuals
with recurrent thromboembolism, multiple hemostatic abnormalities, or
other coexistent circumstantial and/or hormonal risk factors and in
individuals homozygous for the factor V Leiden allele. In these
individuals with a high risk of recurrence, the potential benefits
from long-term warfarin may outweigh the bleeding risks.

Prophylaxis.   In the absence of a history of thrombosis, long-term
anticoagulation is not routinely recommended for asymptomatic
individuals who are heterozygous for the factor V Leiden allele
because the 1-2% per year risk of major bleeding from warfarin is
greater than the estimated <1% per year risk of thrombosis. Since the
initial thrombosis in factor V Leiden heterozygotes occurs in
association with other circumstantial risk factors in 50% of cases, a
short course of prophylactic anticoagulation during exposure to
hemostatic stresses may prevent some of these episodes. Prophylactic
anticoagulation should be considered in high-risk clinical settings
such as surgery, pregnancy, or prolonged immobilization, although
currently no evidence confirms the benefit of primary prophylaxis for
all asymptomatic carriers. Factors that may influence decisions about
the indication for and intensity and duration of anticoagulation
include age, family history, and other coexisting risk factors. Until
prospective trials define more specific guidelines, decisions
regarding prophylactic anticoagulation should be based on the personal
and family history and a risk/benefit assessment in each individual
case.

Pregnancy.  Currently no consensus exists on the optimal management of
women with a factor V Leiden mutation during pregnancy, although
accepted guidelines are similar to those used in women who are not
pregnant. Women with a prior history of venous thrombosis probably
have a higher risk of recurrence during pregnancy, but the true risk
is unknown. The risk is likely higher in women with a prior
spontaneous event, and/or coexisting genetic or acquired risk factors.
One prospective study evaluated the safety of withholding
anticoagulation during pregnancy in 125 women with a history of venous
thromboembolism. In subgroup analysis, women with a previous
spontaneous thromboembolic event and thrombophilia (especially factor
V Leiden), had the highest recurrence rate during pregnancy (20%, odds
ratio of ten) [Brill-Edwards et al 2000].

Women with a factor V Leiden allele and a history of unprovoked or
estrogen-related venous thromboembolic event should receive
prophylactic anticoagulation with unfractionated or low molecular
weight heparin during pregnancy and for six weeks postpartum.
Prophylactic anticoagulation is not routinely recommended in
asymptomatic women with no history of thrombosis, although it is
reasonable to offer it to homozygous women based on the markedly
elevated thrombotic risk associated with high estrogen states.
Pregnant asymptomatic heterozygotes should be warned about potential
thrombotic complications and counseled about the risks and benefits of
anticoagulation during pregnancy. Until more specific guidelines are
defined by prospective trials, decisions about anticoagulation should
be individualized based on the underlying defect and coexisting risk
factors. Asymptomatic women who do not receive anticoagulation should
be followed closely throughout pregnancy, and should be offered
prophylaxis with warfarin for six weeks after delivery, as the
greatest thrombotic risk is in the initial postpartum period.

The current data on antithrombotic therapy in women with inherited
thrombophilia and recurrent pregnancy loss is limited to a few
uncontrolled small case series and a cohort study. In one study, 50
women with thrombophilia (including 20 factor V Leiden heterozygotes)
were treated with enoxaparin throughout 61 subsequent pregnancies. The
live birth rate was 75% with enoxaparin prophylaxis, compared to 20%
in prior untreated pregnancies [Brenner et al 2000]. Another study
evaluated the effect of enoxaparin on subsequent pregnancy outcome in
85 women with inherited thrombophilia (including ten with factor V
Leiden) and unexplained recurrent fetal loss. Enoxaparin prophylaxis
resulted in a live birth rate of 70% compared to 44% in untreated
women, suggesting a threefold greater likelihood of a favorable
outcome. The beneficial effect of anticoagulation was most pronounced
in women with factor V Leiden thrombophilia, although the small number
of individuals studied precluded definitive conclusions [Carp et al
2003]. A prospective randomized trial found that enoxaparin doses of
40 mg/day and 80 mg/day were equally effective, resulting in live
birth rates of 81% and 71%, respectively, compared to a previous
success rate of only 28% in these same women [Brenner et al 2003].
These results suggest that prophylaxis with low molecular weight
heparin may improve pregnancy outcome and provide a rationale for
prospective randomized trials in this group. Until these studies are
completed, antithrombotic prophylaxis should be considered in selected
cases of unexplained recurrent pregnancy loss in women heterozygous
for factor V Leiden, only after an informed discussion of the risks
and limited data suggesting benefit.

Genetic Counseling
Genetic counseling is the process of providing individuals and
families with information on the nature, inheritance, and implications
of genetic disorders to help them make informed medical and personal
decisions. The following section deals with genetic risk assessment
and the use of family history and genetic testing to clarify genetic
status for family members. This section is not meant to address all
personal or cultural issues that individuals may face or to substitute
for consultation with a genetics professional. —ED.

Mode of Inheritance
Heterozygosity for the factor V Leiden allele and some associated risk
for thrombosis are inherited in an autosomal dominant manner.
Homozygosity for factor V Leiden and a greater associated risk for
thrombosis are inherited in an autosomal recessive manner.

Risk to Family Members - Proband Heterozygous for Factor V Leiden
Parents of a proband

In most instances, one parent of a proband heterozygous for the factor
V Leiden allele is also heterozygous for the factor V Leiden allele.
Because of the relatively high prevalence of this allele in the
general population, occasionally one parent is homozygous or both
parents are heterozygous.
Sibs of a proband.  The risk to the sibs of the proband depends upon
the genetic status of the proband's parents.

If one parent of a heterozygous proband is heterozygous, the sibs of
the proband have a 50% risk of being heterozygous for the factor V
Leiden allele.
If one parent is homozygous, the sibs of the proband have a 100% risk
of being heterozygous for the factor V Leiden allele.
If both parents are heterozygous, the sibs of the proband have a 25%
risk of being homozygous for the factor V Leiden allele, a 50% risk of
being heterozygous and a 25% chance of inheriting both normal factor V
alleles.
Offspring of a proband

Each offspring of a proband heterozygous for the factor V Leiden
allele has a 50% chance of inheriting the factor V Leiden allele.
If the proband's partner is heterozygous, each offspring has a 25%
risk of being homozygous for the factor V Leiden allele, a 50% risk of
being heterozygous for the factor V Leiden allele, and a 25% chance of
being homozygous for both normal factor V alleles.
Risk to Family Members - Proband Homozygous for Factor V Leiden
Parents of a proband

In most instances, both parents of an individual homozygous for the
factor V Leiden mutation are heterozygous for factor V Leiden.
Because of the relatively high prevalence of this allele in the
general population, occasionally one parent is homozygous and the
other parent is heterozygous.
Sibs of a proband.  The risk to the sibs of the proband depends upon
the genetic status of the proband's parents.

If the parents of a proband homozygous for the factor V Leiden allele
are heterozygotes, the sibs of the proband have a 25% risk of being
homozygous for the factor V Leiden allele, a 50% risk of being
heterozygous for the factor V Leiden allele and a 25% chance of
inheriting both normal factor V alleles.
If one parent is homozygous for the factor V Leiden allele and the
other parent is heterozygous, the sibs of the proband have a 50%
chance of being homozygous for the factor V Leiden allele and a 50%
chance of being heterozygous.
Offspring of a proband

Each offspring of a proband homozygous for the factor V Leiden allele
has a 100% chance of inheriting one factor V Leiden allele.
If the affected person's partner is heterozygous, each offspring has a
50% chance of inheriting two factor V Leiden alleles, and a 50% chance
of inheriting one factor V Leiden allele.
Other family members of a proband.  The risk to other family members
depends upon the genetic status of the proband's parents. The family
members of a person found to be heterozygous or homozygous for factor
V Leiden are at risk.

Related Genetic Counseling Issues
Informed consent.  Specific informed consent is not generally required
for factor V Leiden genetic testing. However, prior to testing,
individuals should be made aware that genetic test results have
implications regarding risk to other family members and that attendant
issues of confidentiality and possible insurance discrimination may
arise [ACMG Consensus Statement2001].

Testing at-risk family members.  The presence of one or two factor V
Leiden alleles can be identified in asymptomatic at-risk family
members using molecular genetic testing.

The indications for testing at-risk family members are unresolved.
Since heterozygosity for the factor V Leiden allele confers only a
mildly increased risk of thrombosis, routine testing of at-risk family
members is not recommended. Four retrospective studies of relatives of
unselected symptomatic and asymptomatic factor V Leiden heterozygotes
each reported a low thrombotic risk. The results were remarkably
consistent, with the absolute incidence of venous thrombosis ranging
from 0.19%/year to 0.45%/year, compared to 0.10%/year in individuals
without a factor V Leiden allele [Middeldorp et al 1998 , Simioni et
al 1999 , Lensen et al 2000 , Martinelli et al 2000]. Venous
thrombosis occurred in 7-12% of relatives with factor V Leiden
heterozygosity compared to 2-3% of individuals without a factor V
Leiden allele, consistent with other estimates that the lifetime risk
of thrombosis in a heterozygote is approximately 10% [Grody et al
2001]. At least 50% of thrombotic events were associated with other
risk factors, especially pregnancy. One study found a higher
thrombotic risk in relatives from families with a factor V Leiden
allele in which multiple family members had a history of thrombosis.
The absolute incidence of venous thrombosis in heterozygous
first-degree relatives was 1.7%/year, suggesting that a strong family
history is a risk factor for thrombosis [Martinelli et al 2000]. A
systematic review of these four studies found a pooled nearly fourfold
increased relative risk of venous thromboembolism [Langlois & Wells
2003]. Two prospective cohort studies found a slightly higher overall
incidence of VTE in asymptomatic factor V Leiden heterozygotes in the
range of 0.58% to 0.67% per year. The majority (50-75%) of thrombotic
episodes were associated with other risk factors despite the common
use of prophylactic anticoagulation during high risk periods. No
deaths due to VTE occurred in either study [Middeldorp et al 2001 ,
Simioni et al 2002].

The low absolute thrombotic risk in asymptomatic heterozygotes argues
against a general policy of testing at-risk family members. In the
absence of evidence that early diagnosis of the heterozygous state
reduces morbidity or mortality, the decision to test at-risk family
members should be made on an individual basis. Clarification of factor
V Leiden allele status may be beneficial in women considering use of
oral contraception or pregnancy or in families with a strong history
of recurrent venous thrombosis at a young age. At-risk family members
often request factor V Leiden testing prior to exposure to recognized
risk factors or simply from a desire to know their status. Individuals
requesting testing for factor V Leiden and those identified as
heterozygotes should be counseled regarding the implications of the
diagnosis, including the need for prophylactic anticoagulation in high
risk settings and the signs and symptoms that require immediate
medical attention. They should be informed that although the presence
of the factor V Leiden allele is an established risk factor, it does
not predict thrombosis with certainty because the clinical course is
variable even within the same family.

Testing of children.   Currently no consensus exists on the
indications for testing children for the factor V Leiden allele.
Asymptomatic children at risk are not usually tested because
thrombosis rarely occurs before young adulthood, even in homozygous
individuals. Earlier testing may be considered in families with other
known thrombophilic disorders or a strong history of thrombosis at a
young age. (See also the National Society of Genetic Counselors
resolution on genetic testing of children and the American Society of
Human Genetics and American College of Medical Genetics points to
consider : ethical, legal, and psychosocial implications of genetic
testing in children and adolescents.)

Prenatal Testing
Prenatal diagnosis for pregnancies at increased risk is possible by
analysis of DNA extracted from fetal cells obtained by amniocentesis
at 16-18 weeks' gestation * or chorionic villus sampling (CVS) at
about 10-12 weeks' gestation. The diagnosis of factor V Leiden should
be confirmed in an affected family member before prenatal testing is
performed.

Requests for prenatal testing for factor V Leiden are not common.
Differences in perspective may exist among medical professionals and
within families regarding the use of prenatal testing, particularly if
the testing is being considered for the purpose of pregnancy
termination rather than early diagnosis. Although most centers would
consider decisions about prenatal testing to be the choice of the
parents, careful discussion of these issues is appropriate.

*Gestational age is expressed as menstrual weeks calculated either
from the first day of the last normal menstrual period or by
ultrasound measurements.

Molecular Genetics
Information in the Molecular Genetics tables may differ from that in
the text; tables may contain more recent information. —ED.

Molecular Genetics of Factor V Leiden Thrombophilia Gene Symbol
Chromosomal Locus Protein Name
F5 1q23 Coagulation factor V
Data are compiled from the following standard references: Gene symbol
from HUGO; chromosomal locus, locus name, critical region,
complementation group from OMIM; protein name from Swiss-Prot.



OMIM Entries for Factor V Leiden Thrombophilia  188055  THROMBOPHILIA
DUE TO DEFICIENCY OF ACTIVATED PROTEIN C COFACTOR
227400  FACTOR V DEFICIENCY


Genomic Databases for Factor V Leiden Thrombophilia Gene Symbol Entrez
Gene HGMD GeneCards GDB GenAtlas
F5 227400  119896  F5  119896  F5  
For a description of the genomic databases listed, click here.

Normal allelic variants: Haplotype analysis of the factor V gene
strongly suggests that the mutation at nucleotide 1691 was a single
event that occurred 20,000 - 30,000 years ago, after the evolutionary
separation of Caucasians from Asians and Africans [Zivelin et al
1997]. The high prevalence of factor V Leiden among Caucasians
suggests a balanced polymorphism with some type of survival advantage
associated with the heterozygous state. Some investigators speculate
that the mild hypercoagulable state conferred by the mutation might
have had a beneficial effect in reducing mortality from bleeding
associated with childbirth or trauma in pre-modern times [Zivelin et
al 1997]. One retrospective study reported a significantly reduced
risk of intrapartum bleeding complications in women heterozygous for
factor V Leiden compared to women without the mutation [Lindqvist et
al 1998]. Factor V Leiden heterozygotes undergoing elective cardiac
surgery had significantly less blood loss and a lower risk of
requiring a blood transfusion than individuals with a normal factor V
genotype [Donahue et al 2003]. Another study suggested that the
mutation is associated with a fivefold lower risk of spontaneous
intracranial hemorrhage, consistent with the proposed protective
effect [Corral et al 2001]. A study of women who had successful in
vitro fertilization suggested that factor V Leiden enhances embryo
implantation, thereby favoring the early survival of heterozygotes
[Gopel et al 2001]. Analysis of a large randomized trial of
individuals with severe sepsis showed that factor V Leiden
heterozygotes had a threefold greater probability of survival,
confirming animal models of sepsis suggesting a similar survival
benefit [Kerlin et al 2003]. Although each of these hypothesized
beneficial effects could account for the persistence of the mutation,
a survival advantage remains to be confirmed.
Pathologic allelic variants: Two different mutations at the Arg306 APC
cleavage site have been reported, only one of which is associated with
APC resistance. A G-to-C point mutation in the codon for the Arg306
APC cleavage site (factor V Cambridge) was identified in a British
individual with a history of thrombosis and APC resistance in the
absence of the factor V Leiden mutation [Williamson et al 1998]. The
mutation predicts the replacement of Arg with Thr at position 306, the
second of three sequential APC cleavage sites in the factor V
molecule. The same mutation was found in the individual's mother, who
also had an abnormally low APC resistance value. However, it was not
found in 600 other individuals presenting with thromboembolism or in a
population of normal blood donors, suggesting that it is a very rare
factor V variant. This is the only other mutation associated with
hereditary resistance to APC identified to date. A different mutation
in the same codon predicting an R-to-G substitution at position 306 in
factor V was identified in two of 43 Chinese individuals with a
history of thrombosis [Chan et al 1998]. The Arg306Gly mutation was
not associated with APC resistance in the one individual tested with a
coagulation screening assay; the same mutation was identified in one
control individual. Thus, its clinical significance is unclear.
Normal gene product: Coagulation factor V
Abnormal gene product: The point mutation predicts the replacement of
a single amino acid (Arg 506 Gln) at one of three APC cleavage sites
in the factor Va molecule. The mutant factor V Leiden is inactivated
at an approximately tenfold slower rate than normal and persists
longer in the circulation, resulting in increased thrombin generation
and a mild hypercoagulable state, reflected by elevated levels of
prothrombin fragment F1+2 and other activated coagulation markers
[Martinelli et al 1996 , Zoller et al 1996].
Resources
GeneReviews provides information about selected national organizations
and resources for the benefit of the reader. GeneReviews is not
responsible for information provided by other organizations. -ED.

The National Alliance for Thrombosis and Thrombophilia
880 Airport Road
Chapel Hill , NC 27514
Email: nattinfo@nattinfo.org
www.natt.org

National Library of Medicine Genetics Home Reference
Factor V Leiden thrombophilia

March of Dimes
The Thrombophilias and Pregnancy


  Resources Printable Copy

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Author Information
Jody L Kujovich, MD
Assistant Professor, Department of Medicine
Division of Hematology and Medical Oncology
Oregon Health and Science University
Portland

Author History
Scott H Goodnight, MD; Oregon Health & Science University (1998-2004)
Jody L Kujovich, MD (1998-present)

Initial posting: 14 May 1999

Revision History
20 May 2004 (me) Copyedits; updated review posted to live Web site
18 May 2004 (mr) BP edits
4 May 2004 (mr) Author update
26 February 2004 (ca) CD/BP edits to genetic counseling section,
author queries
6 February 2004 (mr) BP edits to MGT section
30 January 2004 (cg) BP edits
18 June 2002 (me) Updated review posted to live Web site
5 June 2002 (tk) Author revisions entered
30 May 2002 (jk) Author revisions received
24 May 2002 (tk) ME copyedits
21 May 2002 (tk) BP update edits
27 April 2002 (tk) Author revisions entered
20 April 2002 (jk) Author revisions received
7 December 2001 (tk) BP edits; new references added
29 November 2001 (jk) Author revisions
25 September 2001 (tk) CD edits
26 June 2001 (ca) BP update edits
14 May 1999 (pb) Copyedits; review posted to live Web site
10 May 1999 (pb) Review
13 April 1999 (jk) Author revisions
2 March 1999 (pb) Review
19 January 1999 (me) BP, BrP/CL edits
19 January 1999 (me) BP, BrP/CL edits
12 January 1999 (ks) CD edits
6 January 1999 (ks) BP edits
29 December 1998 (jk) Original submission

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    I'm unfamiliar with the condition, but think we probably would have
heard something if it was known.
    Way back I remember Socransky was involved in research showing subtle
malfunctions of certain erythrocytes being related to juvenile
periodontitis, but I don't remember anything related to coagulation
function.

Steve