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

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.

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.