Factor V 1691 G>A
The 1000 Genomes Project Database and the genome Aggregation Database (gnomAD) reports global frequencies of 0.6% and 1.73% respectively for the variant A-allele (NIH). Kujovich reports that heterozygosity for the Leiden variant (GA) occurs in 3%-8% of the general US and European populations. The highest heterozygosity rate is found in Europe; the Leiden variant is extremely rare in Asian, African, and indigenous Australian populations.
Factor V Gene Detail
Factor V is considered a key role player in the coagulation cascade as its activated form converts prothrombin to thrombin.
The 1691 G>A (Arg534Gln) polymorphism, alternatively called the factor V Leiden variant, results in factor V being inactivated at an approximately 10-fold slower rate than normal. Factor V with the Leiden variant thus persists longer in the circulation, resulting in increased thrombin generation and a mild hypercoagulable state. Heterozygotes (GA) have a slightly increased risk for venous thrombosis (VTE) whereas homozygotes (AA) have a much greater thrombotic risk.
This risk may increase with combined oral contraceptive (COC) use, hormone replacement therapy (HRT), pregnancy and with age. Women who carry the Leiden variant (A-allele) should avoid oestrogen-containing contraception and HRT, especially if a history of VTE is present.
Factor V 1691 G>A
Factor V is considered a key regulator in the coagulation cascade. Once activated, factor V functions as a cofactor that accelerates clot formation as it converts prothrombin to thrombin. It is mainly synthesised in the liver and is inactivated when cleaved by activated Protein C (aPC) at two aPC sites in factor V. In the presence of what is called thrombomodulin, thrombin acts to decrease clotting by activating protein C; therefore, the concentration and the action of protein C are important determinants in the negative feedback loop through which thrombin limits its activation.
The F5 gene encoding factor V, located in chromosome 1q24.2, contains 25 exons. The 1691 G>A (Arg534Gln) polymorphism is also called the factor V Leiden variant. This variant occurs in an aPC cleavage site in factor V and may result in less efficient aPC cleavage; factor V with the Leiden variant is reportedly inactivated at an approximately 10-fold slower rate than normal due to the amino acid change. Factor V with the Leiden variant 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. The consequences are enhancing the procoagulant role of factor Va and the reduced anticoagulant role of factor V.
Factor V Leiden thrombophilia is the most common inherited form of thrombophilia. Its association with a poor anticoagulant response to activated protein C (aPC) results in an increased risk for venous thromboembolism (VTE). Deep vein thrombosis (DVT) is the most common VTE, with the legs being the most common site. Factor V Leiden is described as an autosomal dominant genetic condition which exhibits incomplete penetrance, meaning that not every person who has the mutation will develop the disease.
The clinical expression of factor V Leiden thrombophilia is influenced by the number of Leiden variants, where heterozygotes (GA) have a slightly increased risk for venous thrombosis and homozygotes (AA) have a much greater thrombotic risk. It is reported however that in addition to genotype, environmental risk factors also play a significant role in thrombotic risk. These include (but is not limited to) pregnancy, central venous catheters, travel, combined oral contraceptive (COC) use and other combined contraceptives, oral hormone replacement therapy (HRT), selective oestrogen receptor modulators (SERMs), obesity, leg injury, and advancing age.
Risk Based On Genotype
Heterozygosity for the Leiden variant (GA) is not associated with an increase in mortality or reduction in normal life expectancy, even in the presence of a history of VTE. The relative risk for venous thrombosis is reportedly increased approximately three- to eightfold in Leiden variant heterozygotes but despite this increase in relative risk, the overall annual incidence of a first VTE is low in heterozygotes (approximately 0.5%).
While individuals homozygous for the Leiden variant (AA) have a higher risk for thrombosis than heterozygotes, the clinical course of an acute thrombotic episode is not considered more severe or more resistant to anticoagulation in homozygotes than in heterozygotes. They do however tend to develop thrombosis at a younger age. Various studies have found that the risk for VTE is increased in Leiden variant homozygotes, respectively by nine- to 80-fold (Rosendaal & Reitsma 2009), nine- to 12-fold (Gohil et al. 2009, Simone et al. 2013) and 20- to 80-fold.
Risk For VTE In Pregnancy
Women heterozygous for the Leiden variant (A-allele carriers) have a five to eight times greater risk of pregnancy-related VTE than women without the variant (GG genotype). The risk is higher in women from families with a history of thrombosis and in women older than age 34 years, with the highest risk of VTE occurs during the first six weeks postpartum.
While heterozygosity for the Leiden variant (GA) increases the relative risk for pregnancy-associated VTE, the absolute risk is low in the absence of other predisposing factors. VTE is estimated to occur in 1% of pregnancies in heterozygotic women; the absolute risk increases to 3% in those with a positive family history of VTE.
In women homozygous for the Leiden variant (AA) the relative risk for pregnancy-associated VTE is increased 17- to 34-fold. The absolute risk of developing pregnancy-related VTE is estimated at 2.2%-4.8% of pregnancies. The risk is higher (14%) in homozygotes with a positive family history and in those older than age 34 years.
It is thought unlikely that a factor V Leiden thrombophilia (i.e., heterozygosity or homozygosity for the Leiden variant) is a major factor contributing to pregnancy loss and other adverse pregnancy outcomes (preeclampsia, foetal growth restriction and placental abruption); research seems contradicting. Kujovich (1999) stated that, at most, factor V Leiden thrombophilia is one of several largely undetermined genetic and environmental predisposing factors contributing to these complications.
A 2010 meta-analysis from Rodger et al. evaluating prospective cohort studies, reported a slightly increased risk of pregnancy loss in women with the Leiden variant (4.2%) compared to those without the variant (3.2%) (odds ratio 1.52). An earlier meta-analysis found that heterozygosity for the Leiden variant is associated with a two-fold increased risk for late unexplained foetal loss and a four-fold higher risk for loss in the second trimester compared to the first trimester.
Although a 2010 systematic review from Rodger et al. found no significant association of preeclampsia or placental abruption with factor V Leiden thrombophilia, a 2012 Danish case-cohort study from Lykke et al. found that heterozygosity for the Leiden variant (GA) increased the risk of severe preeclampsia (odds ratio 1.6), severe foetal growth restriction (odds ratio 1.5), and symptomatic placental abruption (odds ratio 1.7).
In agreement to these results a more recent meta-analysis from Zhang et al. (2016) found that overall, the SNP is significantly associated with preeclampsia. The subgroup analysis by ethnicity revealed that this association remained significant only in Caucasians. The analysis included 16 646 preeclampsia patients and 28 901 normal-pregnancy patients.
Environmental Risk Factors For VTE
Several studies have identified factors that are suggested to influence the relative risk for VTE. These include:
- Combined oral contraceptive (COCs) use have been found to increase risk in heterozygous women, with the risk reportedly much higher during the first year of use than subsequent years. The additive effect of both a Leiden variant (A-allele) and use of COCs was confirmed in multiple studies in which odds ratios for VTE ranged from 11 to 41.
Despite the marked increase in relative risk for VTE, the absolute incidence of VTE may be low because of the low baseline risk for VTE in young women. Since the incidence of VTE increases with age, the absolute risk for VTE in women older than age 50 years is much higher than in younger COC users. The absolute VTE risk is substantially higher in COC users doubly heterozygous for the Leiden variant and the prothrombin 20210 G>A variant or homozygous for either variant.
- Oral hormone replacement therapy (HRT) have been reported to pose a seven- to 25-fold increased relative risk, with higher doses of oestrogen increasing relative risk. Other studies have indicated a two- to four-fold increased relative risk for VTE in healthy postmenopausal users of HRT compared to non-users.
- Transdermal HRT is reported to have a lower relative risk than oral HRT; multiple observational studies consistently found that transdermal HRT did not increase the risk of VTE. There is also evidence that transdermal oestrogen is associated with a lower thrombotic risk than oral oestrogen in women with inherited thrombophilic variants including the Leiden variant. Women with a Leiden variant using transdermal oestrogen had a risk similar to that of non-users with the variant.
- Travelling has been found to increase relative risk by 2-fold; an up to 8-fold relative risk has been reported when travelling ≥ 4 uninterrupted hours.
- Overweight (BMI ≥25 to <30kg/m2) and obesity (BMI ≥30kg/m2) has been reported to pose a 4- to 10-fold and 5- to 12-fold increased relative risk, respectively.
- Age seems to be an independent risk factor for VTE. After the age of 45 years, the lifetime risk increases to 17% (versus 8% in the general population); the highest risk has been found in persons >70 years with a positive family history.
Women who are heterozygous for the Leiden variant (GA) and with a history of VTE should avoid oestrogen-containing contraception and hormone replacement therapy (HRT), whereas women homozygous for the Leiden variant (AA) should avoid oestrogen-containing contraception and HRT with or without prior VTE.
Asymptomatic women heterozygous for the Leiden variant (GA) should be counselled on the risks of oestrogen-containing contraception and HRT use and should be encouraged to consider alternative forms of contraception and control of menopausal symptoms. If they choose to use oral contraceptives, it is recommended to avoid third-generation and other progestins with a higher thrombotic risk. Women electing short-term HRT for severe menopausal symptoms should use a low-dose transdermal preparation, which has a lower thrombotic risk than oral formulations.
Combined oral contraceptives, thrombophilia and the risk of venous thromboembolism: a systematic review and meta-analysis
Van Vlijmen et al, 2016.